e-TC: Development and pilot testing of a web-based intervention to reduce anxiety and depression in survivors of testicular cancer.

e-TC is an online intervention designed to address common psychosocial concerns of testicular cancer survivors. It aims to reduce anxiety, depression and fear of cancer recurrence by providing evidence-based information and psychological intervention. This paper details the development and pilot testing of e-TC. During pilot testing, 25 men (with varying psychological profiles) who had completed treatment for testicular cancer, 6 months to 5 years ago (which had not recurred), used e-TC over a 10-week period and provided quantitative and qualitative feedback on the feasibility and acceptability of the programme. Six men also completed a qualitative interview to provide detailed feedback on their experiences using e-TC. Fourteen men (56%) completed at least 80% of the programme. Participants reported a high level of satisfaction with the programme. Men's limited time was a barrier to programme use and completion, and participants suggested that men with a more recent diagnosis and a higher level of distress may be more likely to engage with the programme. e-TC appears to be a feasible and acceptable online intervention for survivors of testicular cancer. Findings from this study are currently being used to refine e-TC and guide the design of a larger efficacy study.

iCanADAPT Early protocol: randomised controlled trial (RCT) of clinician supervised transdiagnostic internet-delivered cognitive behaviour therapy (iCBT) for depression and/or anxiety in early stage cancer survivors -vs- treatment as usual.

BACKGROUND: This RCT with two parallel arms will evaluate the efficacy of an internet-delivered transdiagnostic cognitive behavioural therapy (iCBT) intervention for the treatment of clinical depression and/or anxiety in early stage cancer survivors. METHODS/DESIGN: Early stage cancer survivors will be recruited via the research arm of a not-for-profit clinical research unit and randomised to an intervention (iCBT) group or a 'treatment as usual' (TAU) control group. The minimum sample size for each group is 45 people (assuming effect size > 0.6, power of 80%, and alpha at .05), but 10% more will be recruited to account for attrition. A solitary or cumulative diagnosis(es) of Major Depressive Episode (current), Generalised Anxiety Disorder, Illness Anxiety Disorder, Panic Disorder, Agoraphobia, and/or Adjustment disorder will be determined using modules from the Anxiety Disorders Interview Schedule for DSM-5. Depression and anxiety levels with be measured via the total score of the Hospital Anxiety and Depression scale (HADS-T), the primary outcome measure. Secondary measures will include the Kessler 10 to measure general distress, the Fear of Cancer Recurrence Inventory (FCRI) to measure the specific fear of cancer recurrence and the Functional Assessment of Cancer Therapy, General Version 4 (FACT-G) for self-report of physical, social, emotional and functional well-being. iCBT participants will complete the measures before lessons 1 and 5, at post-treatment and at 3-month follow-up. The TAU group will complete similar measures at weeks 1, 8 and 16 of the waiting period. Program efficacy will be determined using intent-to-treat mixed models. Maintenance of gains will be assessed at 3-month follow-up. Mediation analyses using PROCESS will be used to examine the association between change in depressive and anxious symptoms over time and changes in FCRI and FACT-G QOL in separate analysis. DISCUSSION: This is the first RCT looking at iCBT specifically for clinical depression and/or anxiety in a cancer population. Findings will help to direct the role of iCBT in streamlined psycho-social care pathways. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12616000231448, registered 19th February 2016 ( www.anzctr.org.au ). This trial protocol is in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.

Heterogeneity of HIV incidence: a comparative analysis between fishing communities and in a neighbouring rural general population, Uganda, and implications for HIV control.

OBJECTIVES: To describe HIV heterogeneity in rural Uganda using incidence data collected between January 2012 and December 2014 among fishing cohort (FC) and in an adjacent rural general population cohort (GPC). METHODS: In the FC, eligible HIV high-risk adults aged 18+ years were enrolled, followed and HIV tested every 3 months. Demographic and sexual behaviour data were also collected. The GPC, approximately 47 km away from the FC, was followed through annual surveys, and sociodemographic and behavioural data collected. A subset of GPC with comparable risk profiles to the FC was selected. We presented sociodemographic and risk profiles and also computed stratified HIV incidence. Cox regression was used to assess factors associated with HIV incidence. RESULTS: Overall HIV incidence was higher in the FC than in the 'high-risk' GPC, 6.04 and 0.56 per 100 person years at risk, respectively, with a rate ratio (RR) of 10.83 (95% CI 6.11 to 19.76). This was higher among those aged 18-24 years, unmarried and those with more than two sex partners in the past year, RR of 15.44, 22.99 and 19.29, respectively. In the FC, factors associated with high incidence in multivariate analysis were duration in the community and unprotected sex. The factors in the GPC were ethnicity, marital status and duration in the community. CONCLUSIONS: We have observed a substantial heterogeneity in HIV incidence. The high incidence in fishing communities is contributing greatly to the overall HIV burden in Uganda, and thus urgent combination prevention efforts are needed towards national goal to reduce HIV epidemic.

Physical symptoms, coping styles and quality of life in recurrent ovarian cancer: a prospective population-based study over the last year of life.

OBJECTIVE: The aim of this study was to describe the trajectory of physical symptoms, coping styles and quality of life (QoL) and the relationship between coping and QoL over the last year of life in women with recurrent ovarian cancer. METHODS: The patient cohort were women recruited to the Australian Ovarian Cancer Study who subsequently experienced recurrent, invasive ovarian cancer and completed at least one psychosocial assessment (optimism, minimisation, hopelessness/helplessness, QoL) during the last year of life (n=217). RESULTS: QoL declined sharply from six months before death. Lack of energy was the most prevalent symptom over three measurement periods (67-92%) and also the most severe. Anorexia (36-55%), abdominal swelling (33-58%), nausea (26-47%) and pain (26-43%) all increased in prevalence and severity towards the end of life. Higher optimism (p=0.009), higher minimisation (p=0.003) and lower helplessness/hopelessness (p=0.03) at baseline were significant predictors of subsequent higher QoL. CONCLUSIONS: Progressive deterioration in quality of life may be an indicator of death within about six months and therefore should be an important consideration in decisions about subsequent treatment. Coping styles which independently predicted subsequent changes in QoL could potentially be targeted by interventions to minimise worsening QoL.

A comparison of the FACT-G and the Supportive Care Needs Survey (SCNS) in women with ovarian cancer: unidimensionality of constructs.

PURPOSE: Health-related quality of life (HRQoL) and unmet needs (needs) questionnaires offer alternative perspectives for assessing cancer patients' concerns. We examined whether the conceptual differences underlying these alternative approaches yield corresponding empirical differences. METHODS: Eight-hundred and seventy-four women with ovarian cancer completed the Functional Assessment of Cancer Therapy scale (FACT-G; HRQoL) and the Supportive Care Needs Survey (SCNS-SF34; needs) every 3 months for 2 years. Correlational analysis, exploratory and confirmatory factor analysis (EFA/CFA), and Rasch analysis tested the relationship between patients' responses to similar domains and similar items across the two questionnaires. RESULTS: Strong correlations were found between items with virtually identical wording (0.67-0.75), while moderate to strong correlations (0.55-0.65) were found for those with very similar wording. EFA identified two common domains across the two questionnaires: physical and psychological. For each common domain, CFA indicated models involving a single construct with systematic variation within each questionnaire fit best. Rasch analysis including very similar items within the physical and psychological domains (separately) demonstrated strong evidence of unidimensionality. CONCLUSIONS: The high degree of similarity between patient responses to items addressing the same or very similar concerns suggests either that HRQoL and needs approaches do not reflect different constructs or that patients may not be able to differentiate between the severity of a concern and the level of need associated with that concern, especially when these are assessed in quick succession.

Choosing between the EORTC QLQ-C30 and FACT-G for measuring health-related quality of life in cancer clinical research: issues, evidence and recommendations.

BACKGROUND: This review aims to assist cancer clinical researchers in choosing between the two most widely used measures of cancer-specific health-related quality of life: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Functional Assessment of Cancer Therapy-General (FACT-G). MATERIALS AND METHODS: Information on QLQ-C30 and FACT-G content, scale structure, accessibility and availability was collated from websites and manuals. A systematic review was undertaken to identify all articles reporting on psychometric properties and information to assist interpretability. Evidence for reliability, validity and responsiveness was rated using a standardised checklist. Instrument properties were compared and contrasted to inform recommendations. RESULTS: Psychometric evidence does not recommend one questionnaire over the other in general. However, there are important differences between the scale structure, social domains and tone that inform choice for any particular study. CONCLUSIONS: Where research objectives are concerned with the impact of a specific tumour type, treatment or symptom, choice should be guided by the availability, content, scale structure and psychometric properties of relevant European Organisation for the Research and Treatment of Cancer versus Functional Assessment of Chronic Illness Therapy modules. Because the FACT-G combines symptoms and concerns within each scale, individual items should always be reviewed within the context of specific research objectives. Where these issues are indecisive, researchers are encouraged to use an algorithm at the end of the current article.

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer.

BACKGROUND: Few data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer. METHODS: Self-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression. RESULTS: Of 892 women, 55% (n=489) used CAM, 6% (n=53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83-3.58, p<0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00-1.10, p=0.049), greater anxiety (OR 1.92, 95% CI 1.16-3.16, p=0.01), not currently smoking (OR 0.64, 95% CI 0.42-0.97, p=0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72-0.94, p=0.005). CONCLUSIONS: The majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.

Screening for genital and anorectal sexually transmitted infections in HIV prevention trials in Africa.

OBJECTIVES: To demonstrate the value of routine, basic sexually transmitted infection (STI) screening at enrolment into an HIV-1 vaccine feasibility cohort study and to highlight the importance of soliciting a history of receptive anal intercourse (RAI) in adults identified as "high risk". METHODS: Routine STI screening was offered to adults at high risk of HIV-1 upon enrolment into a cohort study in preparation for HIV-1 vaccine trials. Risk behaviours and STI prevalence were summarised and the value of microscopy assessed. Associations between prevalent HIV-1 infection and RAI or prevalent STI were evaluated with multiple logistic regression. RESULTS: Participants had a high burden of untreated STI. Symptom-directed management would have missed 67% of urethritis cases in men and 59% of cervicitis cases in women. RAI was reported by 36% of male and 18% of female participants. RAI was strongly associated with HIV-1 in men (adjusted odds ratio (aOR) 3.8; 95% CI 2.0 to 6.9) and independently associated with syphilis in women (aOR 12.9; 95% CI 3.4 to 48.7). CONCLUSIONS: High-risk adults recruited for HIV-1 prevention trials carry a high STI burden. Symptom-directed treatment may miss many cases and simple laboratory-based screening can be done with little cost. Risk assessment should include questions about anal intercourse and whether condoms were used. STI screening, including specific assessment for anorectal disease, should be offered in African research settings recruiting participants at high risk of HIV-1 acquisition.

Identification of a novel, human multilymphoid progenitor in cord blood.

The earliest stages of lymphoid commitment from human pluripotent hematopoietic stem cells have not been defined. A clonogenic subpopulation of CD34(+)CD38(-) cord blood cells were identified that expressed high levels of the CD7 antigen and possessed only lymphoid potential. CD34(+)CD38(-)CD7(+) (CD7(+)) cells uniformly coexpressed CD45RA and HLA-DR; c-kit and Thy-1 expression was absent to low. Clonal analysis demonstrated that single CD7(+) cells could generate B cells, natural killer cells, and dendritic cells but were devoid of myeloid or erythroid potential. In contrast, control CD34(+)CD38(-)CD7(-) (CD7(-)) cells generated both lymphoid and myelo-erythroid cells. The lymphoid potential (generation of lymphoid progeny in bulk and single cell cultures) of CD7(+) cells was equivalent to that of the pluripotent CD7(-) cells. RNA expression studies showed that CD7(+) cells expressed PU.1 and GATA-3, but did not express Pax-5, terminal deoxynucleotide transferase, or CD3epsilon. In contrast to the previously described murine common lymphoid progenitor, the alpha chain of the receptor for interleukin-7 was not detected by fluorescence-activated cell sorting analysis or RNA polymerase chain reaction in CD7(+) cells. These studies identify a clonogenic lymphoid progenitor with both B-cell and natural killer cell lineage potential with a molecular profile that suggests a developmental stage more primitive than previously identified lymphoid progenitors. The CD7(+) phenotype distinguishes primitive human lymphoid progenitors from pluripotent stem cells, thus allowing the study of regulation of early human lymphopoiesis and providing an alternative to pluripotent stem cells for genetic manipulation and transplantation. (Blood. 2001;97:3683-3690)

The role of psychosocial factors in the development of breast carcinoma: Part I. The cancer prone personality.

BACKGROUND: The authors conducted the current study to determine whether personality predisposes some individuals to develop cancer. METHODS: The current study examined the role of personality variables in 2224 older women recalled for assessment after routine mammography in a breast screening program. Using a semiprospective design, subjects completed self-report measures of defense style, locus of control, emotional expression and control, self-esteem, trait anxiety, and state anxiety and depression while waiting for medical examination. Multivariate analysis of variance was used to control for known risk factor variables and to examine differences between 3 control groups (normal tissue controls, benign/cystic controls not requiring biopsy, and benign biopsy controls) and 298 breast carcinoma subjects. RESULTS: No differences were detected between breast carcinoma subjects and controls based on measures of mature, immature, and neurotic defense style; locus of control of behavior; emotional expression-in, emotional expression-out, and emotional control; self-esteem; anxiety; or depression. CONCLUSIONS: The results of the current study found no evidence to support an independent association between these personality measures and the development of breast carcinoma. [See accompanying article on pages 686-97, this issue.]

The role of psychosocial factors in the development of breast carcinoma: Part II. Life event stressors, social support, defense style, and emotional control and their interactions.

BACKGROUND: The evidence supporting an association between life event stress and breast carcinoma development is inconsistent. METHODS: Five hundred fourteen women requiring biopsy after routine mammographic breast screening were interviewed using the Brown and Harris Life Event and Difficulties Schedule. Other psychosocial variables assessed included social support, emotional control, and defense style. Biopsy results identified 239 women with breast carcinoma and 275 women with benign breast disease. Multiple logistic regression analysis was used to distinguish between breast carcinoma subjects and benign breast disease controls based on these psychosocial variables and their interactions. RESULTS: The findings of the current study revealed a significant interaction between highly threatening life stressors and social support. Women experiencing a stressor objectively rated as highly threatening and who were without intimate emotional social support had a ninefold increase in risk of developing breast carcinoma. CONCLUSIONS: Although there was no evidence of an independent association between life event stress and breast carcinoma, the findings of the current study provided strong evidence that social support interacts with highly threatening life stressors to increase the risk of breast carcinoma significantly. [See also accompanying article on pages 679-85, this issue.]

Epidemiological evidence for a relationship between life events, coping style, and personality factors in the development of breast cancer.

OBJECTIVE: Review empirical evidence for a relationship between psychosocial factors and breast cancer development. METHODS: Standardised quality assessment criteria were utilised to assess the evidence of psychosocial predictors of breast cancer development in the following domains: (a) stressful life events, (b) coping style, (c) social support, and (d) emotional and personality factors. RESULTS: Few well-designed studies report any association between life events and breast cancer, the exception being two small studies using the Life Events and Difficulties Schedule (LEDS) reporting an association between severely threatening events and breast cancer risk. Seven studies show anger repression or alexithymia are predictors, the strongest evidence suggesting younger women are at increased risk. There is no evidence that social support, chronic anxiety, or depression affects breast cancer development. With the exception of rationality/anti-emotionality, personality factors do not predict breast cancer risk. CONCLUSION: The evidence for a relationship between psychosocial factors and breast cancer is weak. The strongest predictors are emotional repression and severe life events. Future research would benefit from theoretical grounding and greater methodological rigour. Recommendations are given.

Predictors of breast cancer in women recalled following screening.

BACKGROUND: Established risk factors are associated with between 25 and 56% of breast cancer cases, but the relative importance and relevance to different age groups is unclear. METHODS: This case-control study examines established risk factors in 298 women with breast cancer and 1926 women without breast cancer aged 40-87 who were recalled for assessment following routine mammography. RESULTS: The cancer group were significantly older than the non-cancer group (F1,222 = 107.6; P < 0.0001). Postmenopausal obesity increased the odds of developing breast cancer (OR: 2.35; CI: 1.33-4.16). The breast cancer group were more likely to have used oral contraceptives (OR: 1.50; CI: 1.09-2.05), and women who used contraceptives for more than 10 years in total were at the highest risk (OR: 1.73; CI: 1.13-2.65). Daily consumption of alcohol was also associated with increased risk of developing breast cancer (OR: 1.62; CI: 1.13-2.33). Reproductive factors and a family history of breast cancer did not affect the odds of developing breast cancer and the reasons for these findings are explored. CONCLUSIONS: Results suggest that the effects of weight reduction in reducing postmenopausal breast cancer risk should be assessed.

Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A.

The Hedgehog signal transduction pathway is involved in diverse patterning events in many organisms. In Drosophila, Hedgehog signaling regulates transcription of target genes by modifying the activity of the DNA-binding protein Cubitus interruptus (Ci). Hedgehog signaling inhibits proteolytic cleavage of full-length Ci (Ci-155) to Ci-75, a form that represses some target genes, and also converts the full-length form to a potent transcriptional activator. Reduction of protein kinase A (PKA) activity also leads to accumulation of full-length Ci and to ectopic expression of Hedgehog target genes, prompting the hypothesis that PKA might normally promote cleavage to Ci-75 by directly phosphorylating Ci-155. Here we show that a mutant form of Ci lacking five potential PKA phosphorylation sites (Ci5m) is not detectably cleaved to Ci-75 in Drosophila embryos. Moreover, changes in PKA activity dramatically altered levels of full-length wild-type Ci in embryos and imaginal discs, but did not significantly alter full-length Ci5m levels. We corroborate these results by showing that Ci5m is more active than wild-type Ci at inducing ectopic transcription of the Hh target gene wingless in embryos and that inhibition of PKA enhances induction of wingless by wild-type Ci but not by Ci5m. We therefore propose that PKA phosphorylation of Ci is required for the proteolysis of Ci-155 to Ci-75 in vivo. We also show that the activity of Ci5m remains Hedgehog responsive if expressed at low levels, providing further evidence that the full-length form of Ci undergoes a Hedgehog-dependent activation step.

Stable transduction of quiescent CD34(+)CD38(-) human hematopoietic cells by HIV-1-based lentiviral vectors.

We compared the efficiency of transduction by an HIV-1-based lentiviral vector to that by a Moloney murine leukemia virus (MLV) retroviral vector, using stringent in vitro assays of primitive, quiescent human hematopoietic progenitor cells. Each construct contained the enhanced green fluorescent protein (GFP) as a reporter gene. The lentiviral vector, but not the MLV vector, expressed GFP in nondivided CD34(+) cells (45.5% GFP+) and in CD34(+)CD38(-) cells in G0 (12.4% GFP+), 48 hr after transduction. However, GFP could also be detected short-term in CD34(+) cells transduced with a lentiviral vector that contained a mutated integrase gene. The level of stable transduction from integrated vector was determined after extended long-term bone marrow culture. Both MLV vectors and lentiviral vectors efficiently transduced cytokine-stimulated CD34(+) cells. The MLV vector did not transduce more primitive, quiescent CD34(+)CD38(-) cells (n = 8). In contrast, stable transduction of CD34(+)CD38(-) cells by the lentiviral vector was seen for over 15 weeks of extended long-term culture (9.2 +/- 5.2%, n = 7). GFP expression in clones from single CD34(+)CD38(-) cells confirmed efficient, stable lentiviral transduction in 29% of early and late-proliferating cells. In the absence of growth factors during transduction, only the lentiviral vector was able to transduce CD34(+) and CD34(+)CD38(-) cells (13.5 +/- 2.5%, n = 11 and 12.2 +/- 9.7%, n = 4, respectively). The lentiviral vector is clearly superior to the MLV vector for transduction of quiescent, primitive human hematopoietic progenitor cells and may provide therapeutically useful levels of gene transfer into human hematopoietic stem cells.

The use of a digital imaging system in a dermatologic surgery practice.

BACKGROUND: Digital imaging systems are now commercially available, reasonably affordable, and much improved in quality. OBJECTIVE: To present our 2-year experience with a digital imaging system in Mohs and dermatologic surgery practice and to inform readers of the equipment needed, its cost, uses, advantages, and disadvantages compared with conventional photography. CONCLUSION: The advantages of a digital imaging system include quality images, easy storage and retrieval, and cost-effectiveness. The disadvantages are few: a substantial initial investment and the training of office personnel in its use and maintenance. Uses include monitoring nevomelanocytic lesions, surgical photo documentation, medical records, and a photographic research database.

The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light.

We investigated the activation of c-fos transcription following UV irradiation, a 'stress' stimulus. In both HeLa TK- and NIH 3T3 cells the Serum Response Element is required for efficient UV-induced c-fos transcription, and in HeLa TK- cells the Ternary Complex Factor (TCF) binding site contributes substantially to activation. Consistent with this, UV irradiation activates LexA-TCF fusion proteins more strongly in HeLa TK- than in NIH 3T3 cells. The TCF C-termini of the TCFs are substrates for UV-induced MAP kinases: both the Elk-1 and SAP-1a C-termini are efficiently phosphorylated by the p38 MAPK, but only the Elk-1 C-terminus is a good substrate for the SAPK/JNKs. The specificity and activation kinetics of TCF C-terminal kinases, and the susceptibility of transcriptional activation by LexA-TCF fusion proteins to specific inhibitors of different MAPK pathways, show that both the ERK and p38 MAPK pathways contribute to TCF activation in response to UV irradiation. Activity of both these pathways is also required for the response of the c-fos gene itself to UV stimulation.

Integration of growth factor signals at the c-fos serum response element.

A transcription factor ternary complex composed of serum response factor (SRF) and a second factor, ternary complex factor (TCF), mediates the response of the c-fos Serum Response Element to growth factors and mitogens. In NIH3T3 fibroblasts, TCF binding is required for transcriptional activation by the SRE in response to activation of the Ras-Raf-ERK pathway. We compared the properties of three members of the TCF family, Elk-1, SAP-1 and SAP-2 (ERP/NET). Although all the proteins contain sequences required for ternary complex formation with SRF, only Elk-1 and SAP-1 appear to interact with the c-fos SRE efficiently in vivo. Each TCF contains a C-terminal activation domain capable of transcriptional activation in response to activation of the Ras-Raf-ERK pathway, and this is dependent on the integrity of S/T-P motifs conserved between all the TCF family members. In contrast, activation of the SRE by whole serum and the mitogenic phospholipid LPA requires SRF binding alone. Constitutively activated members of the Rho subfamily of Ras-like GTPases are also capable of inducing activation of the SRE in the absence of TCF; unlike activated Ras itself, these proteins do not activate the TCFs in NIH3T3 cells. At the SRE, SRF- and TCF-linked signalling pathways act synergistically to potentiate transcription.