Psychosocial morbidity in women with abnormal cervical cytology managed by cytological surveillance or initial colposcopy: longitudinal analysis from the TOMBOLA randomised trial.

OBJECTIVE: To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology. METHODS: Women aged 20-59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity. RESULTS: On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI -3.6 to -1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (-2.4; -3.3 to -1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education. CONCLUSIONS: Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women. © 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.

Effect of longer health service provider delays on stage at diagnosis and mortality in symptomatic breast cancer.

PURPOSE: This study explored whether longer provider delays (between first presentation and treatment) were associated with later stage and poorer survival in women with symptomatic breast cancer. METHODS: Data from 850 women with symptomatic breast cancer were linked with the Scottish Cancer Registry; Death Registry; and hospital discharge dataset. Logistic regression and Cox survival analyses with restricted cubic splines explored relationships between provider delays, stage and survival, with sequential adjustment for patient and tumour factors. RESULTS: Although confidence intervals were wide in both adjusted analyses, those with the shortest provider delays had more advanced breast cancer at diagnosis. Beyond approximately 20 weeks, the trend suggests longer delays are associated with more advanced stage, but is not statistically significant. Those with symptomatic breast cancer and the shortest presentation to treatment time (within 4 weeks) had the poorest survival. Longer time to treatment was not significantly associated with worsening mortality. CONCLUSIONS: Poor prognosis patients with breast cancer are being triaged for rapid treatment with limited effect on outcome. Prolonged time to treatment does not appear to be strongly associated with poorer outcomes for patients with breast cancer, but the power of this study to assess the effect of very long delays (>25 weeks) was limited. Efforts to reduce waiting times are important from a quality of life perspective, but tumour biology may often be a more important determinant of stage at diagnosis and survival outcome.

A normal colposcopy examination fails to provide psychological reassurance for women who have had low-grade abnormal cervical cytology.

OBJECTIVE: Worldwide, each year, large numbers of women are referred for colposcopy following low-grade abnormal cervical cytology. Many have no visible abnormality on examination. The risk of cervical intra-epithelial neoplasia grade 2/3 (CIN2/3) in these women is low. It is unknown whether, for women, a normal colposcopy resolves the anxiety which often follows the receipt of an abnormal cytology result. We investigated the prevalence of adverse psychological outcomes over 30 months following a normal colposcopy. METHODS: This cohort study was nested within the UK TOMBOLA randomized controlled trial. Women aged 20-59 years, with recent low-grade cytology, who had a satisfactory colposcopy examination and normal transformation zone, completed the Hospital Anxiety and Depression Scale (HADS) and Process Outcome Specific Measure (POSM) at recruitment and during follow-up (12, 18, 24 and 30 months post-recruitment). Outcomes included percentages reporting significant anxiety (HADS anxiety subscale score ≥11), significant depression (HADS depression subscale score ≥8) or worries about the result of the next cytology test, cervical cancer, having sex, future fertility and general health at each time point (point prevalence) and during follow-up (cumulative prevalence). RESULTS: The study included 727 women. All psychological measures (except depression) had high prevalence at recruitment, falling substantially by 12 months. During follow-up, the cumulative prevalence of significant anxiety was 27% and significant depression was 21%. The most frequently reported worry was that the next cytology test would be abnormal (cumulative prevalence of 71%; point prevalence of ≥50% at 12 and 18 months). The cumulative prevalence values of worries about cervical cancer, having sex and future fertility were 33%, 20% and 16%, respectively. CONCLUSIONS: For some women who have low-grade cytology, a normal colposcopy does not appear to provide psychological reassurance.

The development and evaluation of a questionnaire to assess the impact of vulval intraepithelial neoplasia: a questionnaire study.

OBJECTIVE: To develop and evaluate a questionnaire to assess the burden of vulval intraepithelial neoplasia (VIN) in women. DESIGN: A questionnaire development study. SETTING: Vulval Disorders Clinic serving a regional population. SAMPLE: Fifty-eight women with a histological diagnosis of VIN registered with the Vulval Disorders Clinic. METHODS: A 37-item questionnaire was developed through a comprehensive literature review, consultation with specialist clinicians and pretesting to assess the burden experienced by women. The questionnaire was assessed for validity and reliability against existing questionnaires used in related disease areas. MAIN OUTCOME MEASURES: Spearman correlations were calculated between items in the VIN questionnaire with the scores of the Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS), Sabbatsberg Sexual Self-Rating Scale (SSRS) and the Process Outcome Specific Measure (POSM) to assess the new questionnaire's validity. Internal consistency was measured using Cronbach's alpha. Test-retest reliability was calculated using quadratic weighted kappa. RESULTS: The VIN questionnaire had a high degree of internal consistency (Cronbach's alpha, 0.89). Test-retest reliability was assessed, with most questions showing a quadratic weighted kappa value of 0.5 or above. Most questions showed a stronger correlation with the corrected total VIN score than with HADS anxiety and depression subscales and the SSRS, indicating discriminant validity. Most questions correlated significantly with the DLQI and POSM scores, indicating convergent validity. CONCLUSIONS: Initial assessment of the VIN questionnaire demonstrated that it is a valid and reliable measure of the burden of disease for women. The questionnaire could be used to compare new and existing treatments for VIN or to assess or monitor the impact of care.

Modifiable and fixed factors predicting quality of life in people with colorectal cancer.

BACKGROUND: People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it. METHODS: Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30). RESULTS: Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R(2)=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R(2)=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors. CONCLUSION: Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.

The impact of microinvasive cancer of the cervix on women during follow-up.

The psychologic and psychosexual sequelae of cervical screening and disease are well recognized but most research has focused on women with cervical intraepithelial neoplasia (CIN) or women with early (stage IB) to advanced cervical cancer. There has been little work looking at women with microinvasive cancer as a unique clinical identity. Many of these women have a similar diagnostic, treatment, and follow-up pathway to those with high-grade CIN. This could result in unrecognized and ongoing health concerns. We report on a questionnaire-based case-control study, comparing the concerns of women with microinvasive cervical cancer with those of women with high-grade CIN. Women with microinvasive cancer and controls with CIN2/3 diagnosed between 2000 and 2006, from a geographically defined population, were recruited and invited to complete a postal questionnaire consisting of the Hospital Anxiety and Depression Scale (HADS) and the Process Outcome Specific Measure (POSM). Twenty-eight women diagnosed with microinvasive cancer were identified and 18 participated (response rate 64%). Fifty-eight controls were matched by age and year of treatment with 26 responding (45%). About 18% of women with microinvasive cancer had a HADS depression score of 8 or more, compared to 12% of those with CIN (P = not significant). The HADS anxiety score of 8 or more occurred in 35% of each group. There were no significant differences in terms of POSM results for sexual activity, fertility, and developing cervical cancer in the future between cases and controls. We did not find a difference between women with a previous diagnosis of microinvasive cancer and those with high-grade CIN, in terms of ongoing concerns during their follow-up. We did not identify any additional concerns for women with microinvasive cancer in the care provided in the colposcopy service.

Reasons for participation and non-participation in a randomized controlled trial: postal questionnaire surveys of women eligible for TOMBOLA (Trial Of Management of Borderline and Other Low-Grade Abnormal smears).

BACKGROUND: Better understanding of motivators for, and barriers to, participation in randomized controlled trials (RCTs) in different study populations and settings has the potential to improve participation of historically under-represented groups (eg, women) in future trials. PURPOSE: To investigate reasons why women agreed, or declined, to participate in a RCT. METHODS: In two postal questionnaire-based studies, we investigated women's reasons for participation or non-participation in TOMBOLA, a RCT comparing management policies for low-grade cervical abnormalities. Four-hundred and ninety-two TOMBOLA participants (response rate 56%) completed questionnaires on reasons for participation. One-hundred and thiry-seven women (38%) who declined TOMBOLA participation completed questionnaires on reasons for this. RESULTS: Eighty percent of women reported that one of their reasons for attending their TOMBOLA recruitment appointment was worries about their smear result. Ninety-four percent participated in the RCT because it was a worthwhile contribution to the cervical screening programme and other women; for 70% this was the most important reason. These proportions did not vary by socio-demographic factors. Thirty-two percent thought participation would result in better care. The most common reason for non-participation was preference for follow-up from the woman's GP. Logistical issues (eg, inconvenient appointments, travel time, arranging time off work or child-care) were commonly cited. Fourteen percent were too frightened to participate; this was unrelated to the grade of the recruitment smear. LIMITATIONS: Response rates were not high, but there was little evidence of response bias. Structured questionnaires were used. CONCLUSIONS: Future research should address how best to deliver information to ensure different social groups appreciate potential benefits of RCT participation and provide reassurance regarding fears about participation. Simple strategies (eg, appealing to the altruism of potential participants or offering flexible recruitment clinic locations and times) might enhance RCT recruitment rates. This in turn would ensure best use of research resources thus bringing the greatest benefits to participants and the population.

Psychological effects of a low-grade abnormal cervical smear test result: anxiety and associated factors.

Receipt of an abnormal cervical smear result often generates fear and confusion and can have a negative impact on a woman's well-being. Most previous studies have focussed on high-grade abnormal smears. This study describes the psychological and psychosocial effects, on women, of having received a low-grade abnormal smear result. Over 3500 women recruited to TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) participated in this study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) at recruitment. Socio-demographic and lifestyle factors, locus of control and factors associated with the psychosocial impact of the abnormal smear result were also assessed. Women reported anxiety levels consistent with those found in previous studies of women with high-grade smear results. Women at highest risk of anxiety were younger, had children, were current smokers, or had the highest levels of physical activity. Interventions that focus particularly on women's understanding of smear results and pre-cancer, and/or directly address their fears about cancer, treatment and fertility might provide the greatest opportunity to reduce the adverse psychosocial impact of receiving a low-grade abnormal cervical smear result.

Developing a questionnaire to measure the psychosocial impact of an abnormal cervical smear result and its subsequent management: the TOMBOLA (Trial of Management of Borderline and Other Low-grade Abnormal Smears) trial.

This paper describes the process of developing and testing a new questionnaire, Process Outcome Specific Measure (POSM), including an assessment of its content validity and reliability. The questionnaire was developed within the context of Trial Of Management of Borderline and Other Low-grade Abnormal smears (TOMBOLA) to assess the psychosocial impact of a low-grade abnormal cervical smear result and the subsequent management. A literature search, focus groups and thorough pre-testing involving experts and patients resulted in a short (15-item), easily completed and understood questionnaire. Questions address issues including cancer, health, fertility and sexual concerns. Repeatability was assessed in 110 TOMBOLA recruits using weighted k; all but one of the questions showed levels of reliability near to, or above, 0.5. Cronbach's standardised alpha was 0.73, indicating acceptable internal consistency. Each POSM item was correlated with the anxiety and depression sub-scales of the Hospital Anxiety Depression Scale (HADS). All except one of the questions correlated more highly with the total POSM score than with the HADS sub-scales thus indicating discriminant validity. The POSM will enable comparison of the alternative management policies for low-grade cervical smears in terms of the benefits (or otherwise) perceived by the women managed by these policies.

Cadaveric Tissue Supply to the Commercial Sector For Research: Collaboration between NHS Pathology and NBS Tissue Services in the U.K., Extending the Options for Donors.

The Peterborough Hospital Human Tissue Bank (PHHTB) and National Blood Service Tissue Services (London and South East Zone) (NBSTS) operate within the U.K. National Health Service (NHS) and have a system in place to retrieve cadaveric tissues for commercial sector research. The collaboration meets the aims of PHHTB and NBSTS and is legal, ethical and safe. This paper presents the results of the first 20 successful retrievals referred from NBSTS to PHHTB. Cadaveric retrieval of tissue for research extends the options for donors and their relatives. The research option is particularly welcomed in cases where clinical retrieval for tissue transplantation is contraindicated. We believe the system is applicable to other centres.

Human research tissue banks in the UK National Health Service: laws, ethics, controls and constraints.

National Health Service (NHS) histopathology laboratories are ideally placed to bank cadaveric and surplus surgical tissue to supply the needs of research organisations, whether in the NHS, universities or the commercial sector. This review outlines the constraints to setting up a human tissue bank in an NHS histopathology laboratory, identifies the controls required and answers the question: is it ethical and legal?

Suicide by patients: questionnaire study of its effect on consultant psychiatrists.

OBJECTIVE: To identify the effect of patients' suicide on consultant psychiatrists in Scotland. DESIGN: Confidential coded postal questionnaire survey. PARTICIPANTS: Of 315 eligible consultant psychiatrists, 247 (78%) contributed. SETTING: Scotland. MAIN OUTCOME MEASURES: Experience of patient suicide; the features and impact of "most distressing" suicide and what helped them to deal with it. RESULTS: 167 (68%) consultants had had a patient commit suicide under their care. Fifty four (33%) reported being affected personally in terms of low mood, poor sleep, or irritability. Changes in professional practice were described by 69 (42%) of the psychiatrists-for example, a more structured approach to the management of patients at risk and increased use of mental health legislation. Twenty four (15%) doctors considered taking early retirement because of a patient's suicide. Colleagues and family or friends were the best sources of help, and team and critical incident reviews were also useful. CONCLUSIONS: Suicide by patients has a substantial emotional and professional effect on consultant psychiatrists. Support from colleagues is helpful, and professional reviews provide opportunities for learning and improved management of suicide and its aftermath.

Personal safety and the abuse of staff in a Scottish NHS Trust.

BACKGROUND: An employer's 'duty of care' is enshrined in statute and common law. This responsibility extends to identifying areas of risk to employee's safety and emotional well being. OBJECTIVE: To identify the views of NHS staff on their safety and exposure to assault and other forms of abuse. DESIGN: A survey by questionnaire and semi-structured interview of the staff of an NHS Trust. SETTING: A large Scottish NHS Trust. SUBJECTS: All 5365 staff of the Trust. RESULTS: Two thousand two hundred and ninety four (43%) employees contributed to this survey. With regard to exposure to hazardous substances and serious infection, most staff were satisfied with safety standards and guidelines. Over a 12 month period 23% of the workforce had been assaulted, mainly by patients and 63% had experienced verbal abuse, again, mainly from patients. There were differences among occupational groups but overall 16% had been bullied; 18% had suffered discrimination; 22% had experienced harassment, and 13% had been victimized. Only 42% of individuals reported their most distressing incidents; 56% of them regarded the outcome of their reports as satisfactory. CONCLUSIONS: Staff are generally satisfied with the steps taken to safeguard them against hazardous substances and serious infection. Assault by and abuse from patients is a considerable risk, especially for trained nurses. In terms of bullying, harassment, discrimination and victimization, the abuse of power by colleagues is also a distressing and under-reported phenomenon which needs to be addressed by regular audit and the creation of a climate in which employees feel secure enough to report such abuse and to have faith in the mechanisms set up to deal with such complaints.

Organophosphate poisoning in Perth, Western Australia, 1987-1996.

This study aimed to review the presentation and management of patients with organophosphate poisoning admitted to the four tertiary teaching hospitals in Perth, Western Australia, over a 10-year period. The case notes of all 69 patients admitted with a discharge diagnosis of organophosphate poisoning were reviewed. Twenty-two of 25 patients (88%) attempting suicide were admitted to Intensive Care Units (ICUs), with a mean stay of 7 days (range 1-25 days). All but one were men, and two died. The 44 patients with accidental exposure were mainly children and had a mean stay of 2 days, with only seven going to the ICU. All survived. Complications overall included respiratory failure, convulsions, and aspiration pneumonia. Intubation and ventilation were required in 11 patients (16%), with a mean ventilation duration of 6 days (range 1-25 days). We conclude that deliberate ingestion of organophosphates is considerably more toxic than accidental exposure. Men aged 30-50 years were the most likely to attempt suicide with these agents and had prolonged ICU admissions with significant complications and mortality.

The intracellular phosphorylation of (-)-2'-deoxy-3'-thiacytidine (3TC) and the incorporation of 3TC 5'-monophosphate into DNA by HIV-1 reverse transcriptase and human DNA polymerase gamma.

(-)-2'-deoxy-3'-thiacytidine (3TC) has been shown to be a potent, selective inhibitor of HIV replication in vitro, which requires phosphorylation to its 5'-triphosphate for antiviral activity. The intracellular concentration of 3TC 5'-triphosphate in phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBL) shows a linear dependence on the extracellular concentration of 3TC up to an extracellular 3TC concentration of 10 microM. At this extracellular concentration of 3TC, the resulting intracellular concentration of 3TC 5'-triphosphate is 5 microM. This value is similar to the inhibition constant (Ki) values for the competitive inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and human DNA polymerases (10-16 microM) by 3TC 5'-triphosphate. Since the concentration of 3TC producing 90% inhibition (IC90) of HIV replication in PBLs has been reported to be 76 nM, the antiviral activity of 3TC requires intracellular concentrations of 3TC 5'-triphosphate, which would result in very little inhibition of reverse transcriptase if its sole mode of action was competitive inhibition. This apparent discrepency may be explained by the ability of 3TC 5'-triphosphate to act as a substrate for reverse transcriptase. Primer extension assays have shown that 3TC 5'-triphosphate is a substrate for HIV-1 reverse transcriptase and DNA polymerase gamma, resulting in the incorporation of 3TC 5'-monophosphate into DNA. In the case of DNA polymerase gamma, the product of this reaction (i.e. double-stranded DNA with 3TC 5'-monophosphate incorporated at the 3'-terminus of the primer strand) is also a substrate for the 3'-5' exonuclease activity of this enzyme. This may explain the low levels of mitochondrial toxicity observed with 3TC.

The kinetics of the acid-induced conformational change of influenza virus haemagglutinin can be followed using 1,1'-bis(4-anilino-5-naphthalenesulphonic acid).

1,1'-Bis(4-anilino-5-naphthalenesulphonic acid) (bis-ANS) has been shown by fluorescence spectroscopy to bind to bromelain-cleaved influenza haemagglutinin (BHA). The fluorescence intensity of 1.2 microM bis-ANS in the presence of BHA in its low-pH conformation is twenty-fold higher than in the presence of BHA in its neutral-pH conformation. The use of this probe provides a sensitive method for investigating the kinetics of the irreversible conformational change of BHA induced by low pH. At pH5.0 the reaction is described by a rapid burst followed by a double exponential increase in the fluorescence of bis-ANS, with rate constants of 5.2 +/- 0.9 x 10(-3) sec-1 and 6.7 +/- 1.9 x 10(-4) sec-1. This reaction is sensitive to the presence of tert-butylhydroquinone, an inhibitor of the conformational transition of BHA. The dependence of the reaction rate on pH indicates that the acid-induced conformational change is dependent upon the multiple protonation of the neutral-pH conformation of BHA.

Discovery and analysis of a series of C2-symmetric HIV-1 proteinase inhibitors derived from penicillin.

In order to identify a suitable peptide substrate for human immunodeficiency virus-1 (HIV-1) proteinase, a range of peptides from various cleavage sites within the gag-pol polyprotein were assayed by HPLC for specific cleavage. The peptide with the optimal combination of favorable kinetics and good solubility was based on the N-terminus cleavage site of HIV-1 proteinase (KQGTVSFNF*PQIT). The HPLC assay, using the above peptide, was developed into a rapid isocratic method in order to analyze inhibition kinetics. An assay suitable for high-throughput screening was developed using a radioactively labeled peptide with the same sequence, coupled to a solid phase. Using this assay, a C2-symmetric HIV-1 proteinase inhibitor derived from penicillin was discovered during random screening of a compound library. A chemical synthesis program developed this structure into a series of potent inhibitors. The lead structures were highly selective for HIV-1 proteinase with good antiviral activity in vitro against HIV and no cytotoxicity. The HPLC assay was used to demonstrate that these compounds are competitive tight-binding inhibitors of HIV-1 proteinase.

Pharmacological evaluation of 2-amino-6(7)- and 9-amino-6-trifluoromethylbenzonorbornenes, the conformationally rigid analogues of norfenfluramine in mice.

1. The possible role of conformational requirements which fenfluramine and norfenfluramine must satisfy to elicit its observed pharmacological activities was investigated in mice with the use of four conformationally-rigid norfenfluramine analogues. 2. In this study, both the syn-9-amino and endo-2-amino isomers, which structurally resemble the gauche conformation of norfenfluramine, were found to have little or no effect on spontaneous locomotor activity. 3. On the other hand, the isomers (i.e. the anti-9-amino and exo-2-amino isomers) that mimic the anti conformation of norfenfluramine were capable of causing a decrease in spontaneous motor activity similar to that of norfenfluramine. 4. The analgesic activities of these rigid analogues were also assessed and all of the isomers were found to be weakly analgesic. 5. Only the exo-2-amino isomer exhibited analgesic potency similar to that of fenfluramine. Furthermore all of these compounds were capable of enhancing the analgesic activity of morphine.

A series of penicillin derived C2-symmetric inhibitors of HIV-1 proteinase: synthesis, mode of interaction, and structure-activity relationships.

The C2-symmetric diester 1 was identified by random screening as a novel inhibitor of HIV-1 proteinase. This led to the preparation of a series of related more potent amides from readily accessible penicillins. Many of the compounds showed potent antiviral activity in HIV-1-infected MT-4 cells and an ability to inhibit syncytia formation in infected C8166 cells, with no evidence of cytotoxicity. The compounds showed no activity against other aspartyl proteinases (renin, pepsin, and cathepsin D). Structure-activity relationships support a symmetrical interaction with the enzyme. Pharmacokinetic evaluation of the ethylamide 3 revealed it was subject to rapid plasma clearance and had low oral bioavailability.