Randomised controlled trial of a psychotherapeutic intervention to improve quality of life and other outcomes in people who repeatedly self-harm: FReSH START study protocol.

BACKGROUND: Self-harm is a major public health challenge, and repeated self-harm is common in those attending hospital following an episode. Evidence suggests psychological interventions could help people who self-harm, but few definitive studies have assessed their clinical and cost-effectiveness. Repeated self-harm is associated with poor quality of life, depression, suicide and increased health service costs which justify the development of psychotherapeutic interventions tailored for people with repeated self-harm. METHODS: FReSH START is a multicentre individually 1:1 randomised controlled trial evaluating the clinical and cost-effectiveness of standard care plus psychological therapy or standard care alone for adults (≥ 18 years) presenting at an emergency department (ED) with repeated self-harm. Recruiting 630 participants, it includes an internal pilot, economic evaluation and process evaluation. The intervention will be delivered by mental health staff working in acute settings, with experience of assessing and managing risk in people presenting to emergency services with self-harm. Staff will be trained and supervised to deliver one of three specially adapted therapies: psychodynamic interpersonal therapy, cognitive behavioural therapy or acceptance and commitment therapy. Participants allocated to the intervention will receive one of the adapted therapies according to therapist allocation for up to 6 months via 12 weekly, one to one, 45-50-min sessions. The primary outcome is quality of life measured by the Clinical Outcomes in Routine Evaluation Outcome Measure at 12 months post-randomisation. Secondary outcomes include suicidal intent, depression and cost-effectiveness. Data are collected using hospital attendance records and online/postal/telephone questionnaires at 6 and 12 months post-randomisation, with resource use additionally collected at 3 and 9 months. DISCUSSION: This protocol outlines a randomised controlled trial to investigate whether modified therapies are cost-effective and improve quality of life for people who repeatedly self-harm. Few interventions are proven to be deliverable in the NHS for this population. This study is strengthened by the involvement of qualified mental health workers experienced in managing risk as therapists. TRIAL REGISTRATION: Registered on August 03, 2021. IRAS number: 297939. ISRCTN: https://doi.org/10.1186/ISRCTN73357210 . REC reference: 21/EE/0145. SPONSOR: University of Leeds.

Specific collaborative group intervention for patients with medically unexplained symptoms in general practice: a cluster randomized controlled trial.

BACKGROUND: Patients with medically unexplained symptoms (MUS) are frequent in primary care and substantially impaired in their quality of life (QoL). Specific training of general practitioners (GPs) alone did not demonstrate sustained improvement at later follow-up in current reviews. We evaluated a collaborative group intervention. METHODS: We conducted a cluster randomized controlled trial. Thirty-five GPs recruited 304 MUS patients (intervention group: 170; control group: 134). All GPs were trained in diagnosis and management of MUS (control condition). Eighteen randomly selected intervention GPs participated in training for a specific collaborative group intervention. They conducted 10 weekly group sessions and 2 booster meetings in their practices, together with a psychosomatic specialist. Six and 12 months after baseline, QoL was assessed with the Short-Form 36. The primary outcome was the physical composite score (PCS), and the secondary outcome was the mental composite score (MCS). RESULTS: At 12 months, intention-to-treat analyses showed a significant between-group effect for the MCS (p = 0.023) but not for the PCS (p = 0.674). This effect was preceded by a significant reduction of somatic symptom severity (15-item somatic symptom severity scale of the Patient Health Questionnaire, PHQ-15) at 6 months (p = 0.008) that lacked significance at 12 months (p = 0.078). As additional between-group effects at 12 months, per-protocol analyses showed less health anxiety (Whiteley-7; p = 0.038) and less psychosocial distress (PHQ; p = 0.024); GP visits were significantly (p = 0.042) reduced in the intervention group. CONCLUSIONS: Compared to pure GP training, collaborative group intervention achieved a progressive, clinically meaningful improvement in mental but not physical QoL. It could bridge gaps between general practice and mental health care.

The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland.

Compared to the background population, people with epilepsy tend to have lower rates of education and employment, lower rates of marriage and childbearing, and lower overall socioeconomic status (SES). Disparities in epilepsy care based on sociodemographic factors have been observed in the literature, but it is not known whether any such disparities exist in the UK. The UK Epilepsy and Pregnancy Register is a prospective, observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. Here, we report outcomes of registered pregnancies to women with epilepsy living in Scotland from December 1996 to June 2012, based on the degree of socioeconomic deprivation of their postcode area. The Scottish Index of Multiple Deprivation (SIMD) quintile scores from 2006 were used to determine degree of socioeconomic deprivation, and group 1 (most deprived) and group 5 (least deprived) were compared. There were 1526 pregnancies with complete outcome data to women living in Scotland. Of these, 1453 (95.1%) resulted in a live birth and 68 (4.7%) had a major congenital malformation (MCM). Postcodes could not be reliably identified or verified for an additional three women, who have been excluded from SIMD group analysis. Of all women included in this study, 32.4% were in group 1 and 13.2% in group 5. No difference in MCM rate was observed between the two groups (4.4% in group 1 compared to 4.7% in group 5, p=0.84). Women in group 5 were more likely to take preconceptual folic acid (56.8% compared to 14.0%, relative risk: 4.1; 95% CI: 3.1-5.2) and less likely to have generalized tonic-clonic seizures in pregnancy (13.0% compared to 29.2%, relative risk: 0.4; 95% CI: 0.3-0.7) than those in group 1. Women in group 5 were more likely to be on monotherapy regimens (80.2% compared to 65.9%, relative risk: 1.2; 95% CI: 1.1-1.3), less likely to be on valproate (19.5% compared to 28.0%, p=0.05), and more likely to be on lower doses of the drug (825.9mg/day compared to 1012.0mg/day, p=0.05) compared to those in group 1. Although no change in MCM rate was seen based on SES, differences in treatment between socioeconomic groups do exist, particularly for preconceptual folic acid consumption, AED regimen, and seizure frequency. Greater emphasis on the importance of preconceptual counseling, both to discuss AED choice and folic acid intake, would be of benefit, particularly to those living in areas of high socioeconomic deprivation, to improve equity of healthcare delivery for women with epilepsy in Scotland.

Brief psychodynamic interpersonal psychotherapy for patients with multisomatoform disorder: randomised controlled trial.

BACKGROUND: Multisomatoform disorder is characterised by severe and disabling bodily symptoms, and pain is one of the most common and impairing of these. Furthermore, these bodily symptoms cannot be explained by an underlying organic disorder. Patients with multisomatoform disorder are commonly found at all levels of healthcare and are typically difficult to treat for physicians as well as for mental health specialists. AIMS: To test whether brief psychodynamic interpersonal therapy (PIT) effectively improves the physical quality of life in patients who have had multisomatoform disorder for at least 2 years. METHOD: We recruited 211 patients (from six German academic outpatient centres) who met the criteria for multisomatoform disorder for a randomised, controlled, 12-week, parallelgroup trial from 1 July 2006 to 1 January 2009 (International Standard Randomised Controlled Trial Number ISRCTN23215121). We randomly assigned the patients to receive either 12 weekly sessions of PIT (n = 107) or three sessions of enhanced medical care (EMC, n = 104). The physical component summary of the Short Form Health Survey (SF-36) was the pre-specified primary outcome at a 9-month follow-up. RESULTS: Psychodynamic interpersonal therapy improved patients' physical quality of life at follow-up better than EMC (mean improvement in SF-36 score: PIT 5.3, EMC 2.2), with a small to medium between-group effect size (d = 0.42, 95% CI 0.15-0.69, P = 0.001). We also observed a significant improvement in somatisation but not in depression, health anxiety or healthcare utilisation. CONCLUSIONS: This trial documents the long-term efficacy of brief PIT for improving the physical quality of life in patients with multiple, difficult-to-treat, medically unexplained symptoms.

Depression predicts emergency care use in people with chronic obstructive pulmonary disease: a large cohort study in primary care.

Background: Depression is common in people with chronic obstructive pulmonary disease (COPD) and has been associated with a variety of poor outcomes. A large proportion of health care costs in the UK are spent on emergency care. This study examined the prospective relationship between depression and use of emergency care in patients with COPD managed in primary care. Methods: This was a twelve-month, prospective longitudinal study of 355 patients with COPD in six primary care practices in the UK. Baseline measures included demographic characteristics, depression and anxiety, severity of COPD, presence or absence of other chronic diseases, and prior use of emergency care. Outcome measures were (a) number of emergency department (ED) visits; or (b) an emergency hospital admission in the follow-up year. Results: Older age, number of comorbid physical health conditions, severity of COPD, prior use of emergency care, and depression were all independently associated with both ED attendance and an emergency hospital admission in the follow-up year. Subthreshold depression (HADS depression score 4-7) was associated with a 2.8 times increased odds of emergency hospital admission, and HADS depression >8 was associated with 4.8 times increased odds. Conclusion: Depression is a predictor of emergency care in COPD, independent of severity of disease or physical comorbidity. Even mild (subthreshold) symptoms of depression more than double the risk of using emergency care, suggesting there is a strong case to develop and deploy integrated preventive strategies in primary care that can promote mental health in people with COPD.

The cellular oncogene c-myb can interact synergistically with the Epstein-Barr virus BZLF1 transactivator in lymphoid cells.

Regulation of replicative functions in the Epstein-Barr virus (EBV) genome is mediated through activation of a virally encoded transcription factor, Z (BZLF1). We have shown that the Z gene product, which binds to AP-1 sites as a homodimer and has sequence similarity to c-Fos, can efficiently activate the EBV early promoter, BMRF1, in certain cell types (i.e., HeLa cells) but not others (i.e., Jurkat cells). Here we demonstrate that the c-myb proto-oncogene product, which is itself a DNA-binding protein and transcriptional transactivator, can interact synergistically with Z in activating the BMRF1 promoter in Jurkat cells (a T-cell line) or Raji cells (an EBV-positive B-cell), whereas the c-myb gene product by itself has little effect. The simian virus 40 early promoter is also synergistically activated by the Z/c-myb combination. Synergistic transactivation of the BMRF1 promoter by the Z/c-myb combination appears to involve direct binding by the Z protein but not the c-myb protein. A 30-bp sequence in the BMRF1 promoter which contains a Z binding site (a consensus AP-1 site) is sufficient to transfer high-level lymphoid-specific responsiveness to the Z/c-myb combination to a heterologous promoter. That the c-myb oncogene product can interact synergistically with an EBV-encoded member of the leucine zipper protein family suggests c-myb is likely to engage in similar interactions with cellularly encoded transcription factors.

The bZIP transactivator of Epstein-Barr virus, BZLF1, functionally and physically interacts with the p65 subunit of NF-kappa B.

The Epstein-Barr virus (EBV) BZLF1 (Z) immediate-early transactivator initiates the switch between latent and productive infection in B cells. The Z protein, which has homology to the basic leucine zipper protein c-Fos, transactivates the promoters of several replicative cycle proteins. Transactivation efficiency of the EBV BMRF1 promoter by Z is cell type dependent. In B cells, in which EBV typically exists in a latent form, Z activates the BMRF1 promoter inefficiently. We have discovered that the p65 component of the cellular factor NF-kappa B inhibits transactivation of several EBV promoters by Z. Furthermore, the inhibitor of NF-kappa B, I kappa B alpha, can augment Z-induced transactivation in the B-cell line Raji. Using glutathione S-transferase fusion proteins and coimmunoprecipitation studies, we demonstrate a direct interaction between Z and p65. This physical interaction, which requires the dimerization domain of Z and the Rel homology domain of p65, can be demonstrated both in vitro and in vivo. Inhibition of Z transactivation function by NF-kappa B p65, or possibly by other Rel family proteins, may contribute to the inefficiency of Z transactivator function in B cells and may be a mechanism of maintaining B-cell-specific viral latency.

A preliminary study of a measure of role-play competence in psychodynamic interpersonal therapy.

We report a 15-item role-play competence measure. Ratings by three judges of 34 role plays from psychodynamic interpersonal therapy training showed good inter-rater (.73-.79) and internal reliability (.84-.96). Validity was supported as scores were statistically significantly associated with psychotherapy experience. Most participants achieved satisfactory ratings supporting the training.

Cost-effectiveness of brief psychodynamic-interpersonal therapy in high utilizers of psychiatric services.

BACKGROUND: It is known that a small number of patients with mental health problems have chronic disorders and account for a disproportionate amount of mental health costs. This randomized controlled trial evaluated the cost-effectiveness of psychodynamic-interpersonal therapy vs treatment as usual in patients with mental health problems who were unresponsive to usual treatment. METHOD: Subjects (N = 110) with nonpsychotic disorders unresponsive to 6 months of routine specialist mental health treatment were enrolled in a randomized controlled trial. Sixty-three percent were women, the mean age was 41.4 years, the median duration of illness was 5 years, 68% were unemployed or receiving state benefits because of illness, and 75.5% had a depressive illness. Intervention patients received 8 weekly sessions of psychodynamic-interpersonal psychotherapy. Control patients received usual care from their psychiatrist. Outcome measures included ratings of psychological distress and health status and a detailed economic evaluation. Analysis was conducted on an intent-to-treat basis. RESULTS: Subjects randomized to psychotherapy had a significantly greater improvement than controls in psychological distress and social functioning 6 months after the trial. Baseline treatment costs were similar for both groups. Subjects who received psychotherapy showed significant reductions in the cost of health care utilization in the 6 months after treatment compared with controls. The extra cost of psychotherapy was recouped within 6 months through reductions in health care use. CONCLUSION: These preliminary findings suggest that brief psychodynamic-interpersonal therapy may be cost-effective relative to usual care for patients with enduring nonpsychotic symptoms who are not helped by conventional psychiatric treatment.

Killing Epstein-Barr virus-positive B lymphocytes by gene therapy: comparing the efficacy of cytosine deaminase and herpes simplex virus thymidine kinase.

Epstein-Barr virus (EBV)-positive lymphomas are frequent among immunosuppressed patients. We have examined the feasibility of killing EBV-immortalized B lymphocytes by gene transfer involving the use of "suicide" genes whose expression in target cells renders them susceptible to killing by a prodrug. We examined two gene/prodrug pairs: the Escherichia coli cytosine deaminase (CD) gene with the prodrug 5-fluorocytosine (5-FC), and the herpes simplex virus thymidine kinase (HSV-TK) gene with the prodrug ganciclovir. Retroviral vectors and drug selection were used to obtain CD or HSV-TK expression in cells. Both the CD/5-FC and the HSV-TK/ganciclovir combinations yielded substantial killing of EBV-immortalized B lymphocytes in vitro, although the CD/5-FC regimen had a significantly greater therapeutic margin than the HSV-TK/ganciclovir combination. The CD/5-FC pair, but not the HSV-TK/ganciclovir pair, was shown to have a "bystander killing effect" in vitro. When only 30% of the cells expressed the suicide gene, scid mouse tumors regressed in both the CD/5-FC regimen and the HSV-TK/ganciclovir regimen, documenting an in vivo bystander effect with both regimens. However, a greater percentage of tumors completely regressed with the CD/5-FC regimen. Overall, the sum of our data indicates that the CD/5-FC combination is the more promising regimen for treatment of EBV-associated lymphomas in vivo.

Cloning, expression and sequence analysis of the SphI restriction-modification system.

SphI, a type II restriction-modification (R-M) system from the bacterium Streptomyces phaeochromogenes, recognizes the sequence 5'-GCATGC. The SphI methyltransferase (MTase)-encoding gene, sphIM, was cloned into Escherichia coli using MTase selection to isolate the clone. However, none of these clones contained the restriction endonuclease (ENase) gene. Repeated attempts to clone the complete ENase gene along with sphIM in one step failed, presumably due to expression of SphI ENase gene, sphIR, in the presence of inadequate expression of sphIM. The complete sphIR was finally cloned using a two-step process. PCR was used to isolate the 3' end of sphIR from a library. The intact sphIR, reconstructed under control of an inducible promoter, was introduced into an E. coli strain containing a plasmid with the NlaIII MTase-encoding gene (nlaIIIM). The nucleotide sequence of the SphI system was determined, analyzed and compared to previously sequenced R-M systems. The sequence was also examined for features which would help explain why sphIR unlike other actinomycete ENase genes seemed to be expressed in E. coli.

Cloning and expression of the NaeI restriction endonuclease-encoding gene and sequence analysis of the NaeI restriction-modification system.

NaeI, a type-II restriction-modification (R-M) system from the bacterium Nocardia aerocolonigenes, recognizes the sequence 5'-GCCGGC. The NaeI DNA methyltransferase (MTase)-encoding gene, naeIM, had been cloned previously in Escherichia coli [Van Cott and Wilson, Gene 74 (1988) 55-59]. However, none of these clones expressed detectable levels of the restriction endonuclease (ENase). The absence of the intact ENase-encoding gene (naeIR) within the isolated MTase clones was confirmed by recloning the MTase clones into Streptomyces lividans. The complete NaeI system was finally cloned using E. coli AP1-200 [Piekarowicz et al., Nucleic Acids Res. 19 (1991) 1831-1835] and less stringent MTase-selection conditions. The naeIR gene was expressed first by cloning into S. lividans, and later by cloning under control of a regulated promoter in an E. coli strain preprotected by the heterologous MspI MTase (M.MspI). The DNA sequence of the NaeI R-M system has been determined, analyzed and compared to previously sequenced R-M systems.

Psychosocial status of women requesting breast reduction surgery as compared with a control group of large-breasted women.

The breast has special significance for women but unlike women seeking breast augmentation little research has been carried out on those seeking breast reduction. The few studies to date have not used well-recognized instruments nor appropriate controls. The present study compared 33 patients on a waiting list with 22 large-breasted controls using a semistructured questionnaire and well-validated instruments. Patients experienced greater physical and psychological difficulties but similar social difficulties as compared with the control group. Patients were also more anxious and depressed and had poorer self-esteem, body image, interpersonal functioning, and health status. This study confirms the high psychological morbidity of patients seeking breast reduction.

A long-term follow-up study of patients with ischaemic heart disease versus patients with nonspecific chest pain.

Ninety consecutive patients who were admitted to hospital with acute chest pain were followed-up five years later. At the time of the original admission, all of the patients received a detailed physical and psychiatric evaluation. Seventy-one patients were diagnosed as having ischaemic heart disease, and 19 were diagnosed as having nonspecific chest pain. Patients with nonspecific pain were younger, consumed greater amounts of alcohol, smoked more than their organic counterparts, and were more likely to suffer from psychiatric disorder. The five-year assessment was carried out using a self-report questionnaire. Of the original 71 patients with ischaemic heart disease, 14 had died; 43 questionnaires were returned, 80.2% of the original sample. Sixteen (84.9%) of the patients with nonspecific pain were followed up; none had died. Both groups were predominantly male. The patients with nonspecific pain still smoked more than the patients with ischaemic heart disease, and they had significantly more symptoms of anxiety. The overall prevalence of psychiatric morbidity remained high, however, in both groups. Patients who had psychiatric illness at the time of the original assessment were more anxious at follow-up and more likely to complain of chest pain than those who had been well. Patients with nonspecific chest pain continued to seek treatment on a regular basis from their general practitioners either for chest pain or for other symptoms, but few were in frequent contact with hospital services. The possible preventive effects of psychiatric intervention at an earlier stage in both groups of patients needs to be investigated.

Psychiatric status, somatisation, and health care utilization of frequent attenders at the emergency department: a comparison with routine attenders.

Seventy-seven frequent attenders at an emergency department (ED) in an inner-city hospital in the UK (defined as seven or more visits in the previous 12 months) were compared with 182 patients who were attending the same department on a routine basis. Patients completed the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and the Short Form (SF)-36. Information was obtained on 64% of the frequent attenders and 45% underwent a detailed psychiatric assessment. Of the frequent attenders, 45% had psychiatric disorder and 49% had some form of an alcohol-related disorder. Compared with routine attenders, frequent attenders reported lower health status, had more psychiatric disorder (odds ratio: OR=8.2, 95% confidence interval: CI=3.8--18.1), had more general hospital admissions (OR=19.9, 95% CI=8.3--47.8), more psychiatric admissions (OR=167.5, 95% CI=9.5--2959.0), and more GP visits (95% CI for difference=-10.2 to -5.7). There was no evidence that frequent attenders had more somatisation than routine attenders. Specific treatment and management strategies need to be developed for this group of patients, although a substantial proportion may be difficult to engage in the treatment process.

Referral of Asian patients to a GI clinic.

This study compared gastrointestinal (GI) symptoms and psychiatric morbidity in consecutive new out-patients presenting to a district general hospital. In a 6-month period 36 patients of South Asian origin were referred to the clinic. They were compared in terms of GI symptoms and psychiatric morbidity with white European controls, both with a large sample of clinic attenders, and with a subsample of 36 matched for age, gender, and diagnosis. A total of 72% (26 of 36) of Asian patients had functional GI disorders compared to 48% (42 of 88) of white patients (p < 0.05). However, comparisons of matched patients showed that Asian patients with functional GI disorders had less severe GI symptoms than the matched white patients, and fewer had psychiatric disorder (23% of Asians and 42% of white Europeans). These results suggest that the threshold for referral for Asian patients with functional GI disorders to hospital clinics is lower than for white patients. Detection and management of somatization in Asian patients in primary care need to be improved, and referral patterns of general practitioners need to be explored in future research.

Costs of antidepressant overdose: a preliminary study.

There is ongoing debate regarding the relative cost effectiveness of different classes of antidepressants. Although factors such as tolerability and discontinuation rates have been taken into account, there has been little consideration of the cost of overdose. In the current study we examined the cost of antidepressant overdose at four teaching hospitals over a four-week period and found that the cost of selective serotonin reuptake inhibitor overdose was less than half that of tricyclic anti-depressant overdose. The cost of overdose is often ignored and should be considered in future analyses of the cost effectiveness of different antidepressant prescribing policies in primary care.

New techniques for liquid chromatography in open-tubular columns.

Methods for sample introduction, capillary column fabrication, and on-column detection are discussed. A new cross-linked polymer stationary phase coating (based on similar coatings for capillary gas chromatography) is described. Results of separations of urinary components using 16-mum open-tubular columns and electrochemical detection and laser-induced fluorescence detection are shown.

Best practice guidelines for the management of women with epilepsy. The Women with Epilepsy Guidelines Development Group.

Clinical guidelines for the treatment of epilepsy have been published. A statement on management issues for women with epilepsy has recently been produced by the American Academy of Neurology which has raised awareness of the issues facing women with epilepsy. The communication presented here aims to review current literature on specific issues relating to women with epilepsy, and proposes graded recommendations for its management within a UK health care framework.

Soft occlusal splint therapy in the treatment of migraine and other headaches.

Fifty-seven patients suffering from migraine, tension headache or tension vascular headache were prescribed a soft occlusal splint for night-time wear. Dental, psychosocial/psychiatric and neurological data were recorded prior to commencement of therapy and at the conclusion of a 3 month treatment period. A statistically significant number of patients presenting with migraine or tension vascular headache experienced marked improvement or complete relief of headache symptoms, but most patients suffering from tension headache failed to benefit from splint therapy. A majority of patients displaying intercurrent features of craniomandibular dysfunction experienced reduction in these symptoms also. There was a statistically significant association between TMJ improvement and headache type. Prior to treatment, patients who subsequently benefited from splint therapy in terms of headache improvement had experienced significantly fewer headaches than patients who failed to respond, although headache intensity and duration were similar in both groups. It is suggested that headache type and frequency may be prognostic indicators of the likely success of dental splint therapy in treatment of headache. Nevertheless, the use of occlusal splints in the treatment of patients complaining of headache in the absence of evidence of craniomandibular dysfunction should not be embarked upon until medical examination has excluded the possibility of organic neurological disorder.