abstract: The availability of complete genomic sequences of *Saccharomyces cerevisiae* has catalyzed a cultural change in the practice of yeast biology, providing opportunities to develop high throughput techniques to define protein function, to define drug targets, and to discover and characterize drugs.
author: Charles Brenner
date: 2000
institute: 1Kimmel Cancer Center, Thomas Jefferson University, 233 South Tenth Street, Philadelphia, PA 19107, USA. E-mail: firstname.lastname@example.com
references:
title: A cultivated taste for yeast

For decades, yeast biology has been dually justified as an effort to understand fully the cellular processes of a group of single-celled eukaryotes and for its potential to lead to advances in human health. Sequence-based trees of life provide compelling evidence that plants, animals and fungi - once considered three primary kingdoms in a five-kingdom tree - are closely related branches within the eukaryotic domain \[1\]. It is well known that homologs of proteins first identified for key roles in yeast cell-cycle control \[2\], secretion \[3\] and pro-hormone processing \[4\] play similar roles in humans. Furthermore, similarities between fungal, animal and plant cells have created challenges in developing fungal-directed antibiotics that are not toxic to hosts. Although yeast biology has illuminated many processes in yeast and human cells by homology, the yeast cell has also become a laboratory of heterology. In the 1980s, heterologous use of yeast typically referred to protein production \[5\]. In the 1990s, legions of researchers were introduced to yeast two-hybrid systems to identify binding partners of proteins expressed in yeast \[6\]. Although it is too early to predict the leading heterologous use of yeast of the next decade, screens and selections to identify small molecules that act on proteins expressed in yeast hold tremendous promise \[7\]. The power of combinatorial chemistry to screen huge numbers of drugs can now be multiplied by the power of yeast genetics to assay genetic variation. At a recent Cambridge Healthtech Institute meeting in Miami entitled 'Exploiting Yeast Molecular Biology for Therapeutics' (January 20-21, 2000) \[<http://www.healthtech.com/conference/yst/yst.htm>\], some of the latest homologous and heterologous uses of yeast biology were presented, along with new methods for studying yeast biology that became conceivable in the post-genomic era.

# Given a substrate, find the enzyme

Thousands of yeast genes and their corresponding products were identified by classical genetic approaches that began with identification of mutant phenotype and progressed 'forward' to the gene and product. Thousands of other genes were discovered by 'reverse' genetic approaches, in which mutants were obtained last. The original reverse genetics experiments were fractionation-based; one purified a protein of interest, sequenced it, and then cloned and disrupted the corresponding gene (for example, see \[8\]). More recently, reverse genetic approaches have been driven by identification of homologous sequences (for example, see \[9,10,11\]). The availability of complete genomic information has made possible a new type of reverse genetics not driven by sequence similarity but rather based on a novel fractionation scheme.

For example, when Mark Martzen, Elizabeth Grayhack and Eric Phizicky at the University of Rochester set out to identify an enzyme, they began in the classical manner by developing an assay to screen for activity. Rather than fractionating a large, single yeast lysate to identify the enzyme by biochemical means, these researchers used a set of yeast strains carrying fusions of glutathione-S-transferase (GST) to 6,080 open reading frames (ORFs) \[12\]. The GST fusions, developed in the laboratory of Stanley Fields at theUniversity of Washington \[13\], were grown in 64 pools, each containing 95 ORF-GST fusions plus one control GST construct. To identify the gene responsible for an enzyme activity of interest, Martzen and colleagues first screened the 64 pools to identify which one contained the activity. Because each pool originated from constructs held in a 96 well plate, they then screened the 8 rows and 12 columns from the identified plate. The single point of intersection of pooled rows and pooled columns defines the single ORF responsible for an activity. The first publication from the Martzen group using this technique described three enzymes identified in this way \[12\], and the group's biochemical genomics scoreboard now includes a DNA-binding protein and numbers 12 additional enzymes, several of which carry out RNA splicing reactions.

# Given an enzyme, validate it as a drug target

In humans, elevated serum homocysteine concentration is associated with vascular, skeletal and neurological disorders. The most common genetic basis for clinical presentation of severe hyperhomocysteinemia is cystathionine β-synthase (*CBS*) deficiency, found in 1 child in about 300,000 \[14\]. Moreover, levels of homocysteine vary in populations and there is strong epidemiological linkage between elevated total homocysteine levels and vascular disease and stroke \[15\]. Whereas 50% of *CBS*-deficient patients respond to high doses of vitamin B6, and vitamin B6 can also reduce total homocysteine in the majority of the human population, a specific drug that could boost Cbs enzyme activity in *CBS*-deficients and in those at risk for stroke might improve the quality of life for many people. Warren Kruger of the Fox Chase Cancer Center has developed a simple yeast-based assay to phenotype human *CBS* genes and has validated mutant forms of Cbs as targets that could be remedied by drugs. Wild-type human *CBS* coding sequences complement the cysteine deficiency of *S. cerevisiae cys4* deletion mutants, and loss-of-function alleles of human *CBS* fail to complement *cys4* \[16\]. In the course of cloning new *CBS* alleles, Kruger's laboratory amplified a patient's *CBS* genes and recovered a large number of yeast transformants that were cys^-^ and two that were CYS^+^. The two CYS^+^ isolates contained PCR-induced intragenic suppressor mutations of the patient's loss-of-function allele. Both mutations resulted in truncation of an inhibitory carboxy-terminal domain. Nearly all *CBS* patients carry missense mutations and nearly all of these alleles are suppressed by deletion of the carboxy-terminal domain \[17\]. At the Miami meeting, Kruger presented data showing that a variety of point mutations in the carboxy-terminus suppress the hypomorphic phenotypes of *CBS* mutations and that carboxy-terminal suppressors are not allele-specific. Thus, chemical inactivation of the carboxy-terminal domain of Cbs should be achievable and should boost the function of low-activity enzymes. Furthermore, the combinatorial chemist has a choice of primary screens: increase mutant Cbs enzyme activity *in vitro* or generate prototrophy in a *cys4* yeast strain carrying mutant human *CBS*.

# Given a target, find a drug

Kathleen Young of Wyeth-Ayerst Inc. spoke about her group's efforts to find 'disinactivators' of a human potassium channel, Kv1.1/Kvβ1. Inactivation of such channels, mediated by an interaction between the S4-S5 cytoplasmic linker domain of the α subunit and the amino-terminal inactivation ball of the β subunit \[18\] might be associated with seizures and hippocampal ischemia \[19\]. For this reason, small molecules that block the association of specific α and β subunits are considered to have therapeutic potential. As demonstrated earlier with calcium channel fragments \[7\], two-hybrid interactions can be constructed to produce growth inhibition such that drugs that block the interaction restore growth. The new screen for potassium channel disinactivators involved more than 176,000 compounds and has apparently identified a compound, WAY-349, with *in vitro* efficacy and specificity for the Kv1.1/Kvβ1 channel.

# Given a drug, find the target

Although protein-target-directed screening has become the predominant way to identify small molecules today, the majority of approved drugs were identified on the basis of animal or cellular assays. In fact, most of the classical compounds that owe their roots to botanicals and other natural products were originally identified by human self-medication. Thus, it should come as no surprise that a great many drugs have modes of action that are not understood. John Phillips and his colleagues at Rosetta Inpharmatics Inc. use two genomic methods to clarify the mode of action of drugs. First, they have developed a complete set of promoter fusions to the green fluorescent protein of *Aequoria victoria* that allows them to monitor the effect of a small molecule on the expression of each yeast gene \[20\]. Administration of a drug to yeast strains transformed with the set of reporter constructs provides a fluorescent profile of the genes that become activated or repressed in response to a drug. In the best cases, such as that of *erg11*, the ergosterol-starved gene expression profile of *erg11* mutant cells is indistinguishable from that of cells treated with the antifungal drug clotrimazole. Second, they test the drug sensitivity \[21\] of a large and growing set of strains that are heterozygous for individual open reading frames \[22,23\]. Because each gene disruption strain carries two unique 20 nucleotide 'barcodes', deletion mutants can be maintained in a pool \[22,23\]. Upon drug administration, the relative viability of each deletion strain can be assessed by amplification of barcodes from the pooled strains using fluorescently-labeled PCR primers and array hybridization to a DNA chip containing the barcode oligonucleotide probes \[21\]. Particular deletion mutants that are more sensitive to a drug than the majority of deletion mutants produce a less fluorescent signal upon drug administration and are identifiable by losses of particular barcode signals. The most drug-sensitive strains are those in which the gene products targeted by the drugs have been rendered heterozygous \[21\]. This method is complementary to the classical method of cloning the target by virtue of multicopy-plasmid-dependent resistance \[24\]. The advantage of the new method is that it is highly parallel. New compounds can be profiled with ease, and can be used to identify not only primary and secondary targets via sensitivity \[25\] but, additionally, loss-of-function mutations that result in drug-resistance.

# Given a pathogenic fungus, find a drug target

*Candida* species are among the most common fungal pathogens to humans. *C. albicans*, which is asexual and diploid, is refractory to 'forward' or classical genetics though *C. glabrata* is a haploid and, thus, conditionally essential genes or genes essential for adhesion to human epithelial cells can be identified by forward mutagenesis and screening. Having developed methods for homologous and nonhomologous integrative transformation in *C. glabrata* \[26\], Brendan Cormack (Johns Hopkins University) selected 96 40mer oligonucleotide barcodes and integrated them into the disrupted *ura3* locus of a *C. glabrata* strain. Each of these barcoded strains was then subjected to random insertional mutagenesis with the *S. cerevisiae URA3* gene and 100 independent URA^+^ integrants were frozen away for each barcoded strain \[27\]. In each strain, the URA3 insertion is expected to have affected a different gene. By picking one transformant from each of the 96 barcoded transformations, Cormack was able to assemble 100 pools each containing an independent *URA3* insertion in a uniquely identifiable strain.

Cormack has already described a screen in which 50 of the pools, representing as many as 4,800 independent *C. glabrata* mutants, were passaged through an adherence assay on human cultured epithelial cells. By probing a DNA 'macrochip' (a nylon filter the size of a 96 well plate on which the 96 barcode oligonucleotides were spotted) with radioactively labeled barcode PCR reactions from *C. glabrata* cells that grew on human cells, Cormack identified 16 mutants that failed to adhere. Of these, 14 contained insertions in the same gene, named *EPA1* for epithelial adhesin, a calcium-dependent lectin with a consensus sequence for addition of a glycosyl-phosphatidylinositol anchor \[27\]. Cormack also presented data showing that pools of barcoded mutant *C. glabrata* strains can be passaged through a mouse in the primary mutant hunt: 96 mutants being screened per animal. Cormack's approach of barcoding the cells to be mutagenized rather than linking the barcode to the mutants makes his barcodes reusable and independent of specialized array hybridization equipment.

Though the yeast genome has been complete for four years, the majority of yeast gene functions are poorly characterized. Many of the approaches presented in Miami have the potential to assign functions to significant portions of the yeast proteome. As knowledge of yeast cell biology expands, one can expect greater light to be reflected on all eukaryotes and further cultivation of yeast for pharmacological applications.


abstract: Psychosocial interventions are an essential part of the treatment for people with severe mental illness such as schizophrenia. The criteria regarding what makes an intervention "evidence-based" along with a current list of evidence-based interventions are presented. Although many evidence-based interventions exist, implementation studies reveal that few, if any, are ever implemented in a given setting. Various theories and approaches have been developed to better understand and overcome implementation obstacles. Among these, merging two evidence-based interventions, or offering an evidence-based intervention within an evidence-based service, are increasingly being reported and studied in the literature. Five such merges are presented, along with their empirical support: cognitive behavior therapy (CBT) with skills training; CBT and family psychoeducation; supported employment (SE) and skills training; SE and cognitive remediation; and SE and CBT.
author: Tania Lecomte; Marc Corbière; Stéphanie Simard; Claude Leclerc[^1]\*Author to whom correspondence should be addressed; E-Mail: <firstname.lastname@example.com>; Tel.: +1-514-343-6274.
date: 2014-11-06
institute: 1Department of Psychology, University of Montreal, C-358, 90 Vincent d'Indy Street, C.P. 6128, Succ Centre-Ville, Montreal, QC H3C 3J7, Canada; E-Mail: <firstname.lastname@example.com>; 2Centre for Action in Work Disability Prevention and Rehabilitation, School of Rehabilitation, Université de Sherbrooke, 150 Place Charles Le Moyne, Bureau 200, Longueuil, QC J4K 0A8, Canada; E-Mail: <firstname.lastname@example.com>; 3Université du Québec à Trois-Rivières, 3351 Boul Des Forges, Trois-Rivières, QC G9A 5H7, Canada; E-Mail: <email@example.com>
references:
title: Merging Evidence-Based Psychosocial Interventions in Schizophrenia

# 1. Introduction

Psychosocial interventions are an essential part of the treatment and recovery of people with severe mental illness such as schizophrenia. It is well-accepted that medication alone is not sufficient to help with the recovery and various issues a person might encounter when attempting to lead a satisfying life in the community. Some practices have gathered sufficient empirical data to be strongly recommended by national guidelines such as the PORT (Patient outcome research team) \[1\], or the NICE (TheNational Institute for Health and Care Excellence) \[2\] guidelines in the UK, whereas others are considered promising until more studies support its effect. In order for a psychosocial practice, namely an intervention or program (an intervention is specific treatment with a targeted therapeutic aim whereas a program typically includes various interventions), to be considered evidence-based, it must not only have accumulated sufficient empirical proof of its efficacy (often in the context of at least two randomized controlled trials) but it must answer a need (such as improve functioning, overcome a deficit or help to cope with symptoms) and be standardized in order to be easily replicable \[3\]. The 2009 PORT report on psychosocial practices for schizophrenia highlighted eight interventions or programs that could be considered evidence-based \[1\]. These were in terms of interventions: family psychoeducation, cognitive behaviour therapy, social skills training, weight management, and token economy. In terms of programs, they described: intensive community treatment, supported employment and integrated dual-disorder programs (with first episode programs almost meeting criteria). Since, Mueser *et al.* \[3\] has added cognitive remediation, which has demonstrated in various meta-analyses its efficacy in helping individuals overcome cognitive deficits in areas such as memory, attention or problem solving. Although all of the above-mentioned interventions and programs are considered evidence-based and can truly improve the lives of people with severe mental illnesses, implementation studies reveal that few, if any, are ever implemented in a given setting \[4\]. For some interventions, this is understandable—for instance token economy is only effective in changing problematic behaviors when used in a closed and controlled environment, like a forensic ward \[5\]. However, most of the other interventions and programs have demonstrated positive effects in improving symptoms, deficits, and community functioning and are under-utilized. A recent review on implementation of evidence-based psychosocial interventions and programs in psychiatry describes various strategies that have been used in order to improve implementation of one or many evidence-based practice \[4\]. Of the most common strategies, large demonstration projects and effectiveness trials run by researchers, broad service reforms based on new government policies and national agency-led initiatives were identified. Few of these implementation strategies have been studied over the long-term, and fewer even have considered consumer outcomes \[4\]. Other smaller-scale implementation strategies have also been developed, when large-scale funding was not available. For instance, supported employment programs' implementation have been facilitated by a group of researchers and clinicians \[6\] offering standardized training, consultation and encouraging the use of their implementation fidelity scales (The *Quality of Supported Employment Implementation Scale* (QSEIS) \[7\] or the *Individual Placement and Support* (IPS) fidelity scale \[8\]. In the UK, US and Canada, the implementation of CBT for psychosis has been improved by offering the clinical training to mental health professionals from various backgrounds (e.g., nurses, occupational therapists), offering structured manuals, and brief training sessions \[9,10\] rather than limiting the treatment delivery to clinical psychologists.

Another approach to improving implementation of evidence-based psychosocial interventions or programs that is being seen more and more in the literature, particularly in the last decade, is to merge two evidence-based interventions, or to offer an evidence-based intervention within an evidence-based program. Are considered merges both: (a) the simultaneous delivery of two practices (two interventions or an intervention and a program) and, (b) modified practices: interventions changed in order become integrated with another intervention or within a program. In settings with limited means, offering such merges has the advantage of targeting more than one therapeutic goal at once (e.g., cognitive distortion and work integration). Some of the merges have been developed in order to adapt an evidenced-based intervention to a specific population group or setting (such as older consumers). However, most of the merges have been developed with the hope of improving the effectiveness of an evidenced-based program by adding an empirically recognized intervention. It is important to mention that few of the merges presented here simply "co-deliver" interventions—most are well-integrated merges or at least aim at truly integrating the interventions and programs together. The following are descriptions of such merges.

# 2. Cognitive Behavior Therapy (CBT) and Social Skills Training

Granholm and colleagues \[11,12\] have merged two evidence-based psychosocial interventions to cater to the specific needs of aging individuals with psychosis who might be struggling not only with symptoms but also with social and cognitive deficits. CBT for psychosis has been studied in over 40 randomized controlled trials and various meta-analyses since the first promising studies of the 1990s \[13\]. Overall, most studies have found that CBT for psychosis is effective in reducing symptoms and improving other indexes of well-being, often with stronger results compared to other interventions overtime than at post-treatment \[14,15,16\]. However, as in most psychotherapy studies, the most rigorous studies often reveal smaller effect sizes than the non-controlled studies \[17\]. CBT for psychosis aims at modifying dysfunctional beliefs by helping the person understand the link between perceptions, beliefs and emotional and behavioural reactions. CBT also helps the person question the evidence supporting his beliefs (whether they are psychotic or not). Furthermore, CBT brings the person to self-observe himself, his thoughts and behaviors, and explores various coping strategies the person might use when dealing with distressful thoughts or voices. Finally, CBT for psychosis takes into account cognitive biases a person might have and aims at modifying those biases, by seeking alternatives instead of jumping to conclusions, for instance.

CBT for psychosis has been adapted for various clienteles, used with individuals at high risk of developing psychosis, individuals with early psychosis as well as older individuals with a long history of schizophrenia. This latter group was of particular interest for Granholm and colleagues \[12\] who wished to offer CBT for psychosis in a format that would be appealing and adapted to clients who were often isolated, and who might have difficulties grasping some CBT concepts, given their cognitive deficits. They therefore decided to include social skills training to the CBT treatment and offer the merged treatment in a group format.

Social skills training has been around since the 1980s in the USA and was considered especially useful for helping people reintegrate society after a long period of institutionalization. The goal behind skills training is to offer skills that are deemed essential to interact with others, manage one's medication and symptoms, as well as problem solve in different contexts. Skills training is based on Bandura's self-efficacy theory \[18\] and uses repetition and positive reinforcement to help people acquire and remember new skills. To date, over 23 randomized controlled trials have shown that skills training can help acquire skills, decrease negative symptoms, and has a moderate impact on independent living skills \[19,20\]. Skills training can be offered individually but works best in groups, with the use of multiple role-plays preparing for real-life interactions.

## Merging CBT and Skills Training

Granholm and colleagues \[11,12\] developed a group CBT/skills training approach that focuses on CBT for psychosis techniques, such as checking for facts, but presents these in a skills training manner (*i.e.*, a lot of repetition, wallet cards with key words/concepts, use of a big flag in the group to "flag" the beliefs without apparent facts or proof). The group included modules that were repeated over time, enabling the participants to go over the content more than once and allowing new participants to enter the group at any given moment. Although the results did not show an improvement in positive symptoms, it did show improvements in functioning and negative symptoms \[11,12\]. Of importance, the participants were able to remember the concepts and CBT techniques regardless of the severity of their cognitive deficits.

# 3. CBT and Family Psychoeducation

Leclerc and Lecomte \[21\] have recently published promising preliminary data on 40 family members who received a merged group CBT/psychoeducation family intervention. Family intervention, in particular family psychoeducation, is recognized as one of the evidence-based interventions with the most empirical support, especially regarding decreasing rehospitalization rates \[3\]. More than 50 randomized controlled trials have been published to date supporting the effects of family psychoeducation on increased medication adherence, and decreased stress and symptoms in those receiving psychiatric care \[15,22\]. As for their family members, these same studies report decreased perceived burden and psychological distress. Most family interventions last an average of six to nine months and offer: information on symptoms and mental illness, recommendations for dealing with crises, emotional support, and coping skills to deal with symptoms and mental illness \[23\]. Family interventions can be offered to each individual family or multiple families together, with or without the family member receiving psychiatric care. Many family intervention manuals were developed in the 1990s and do not address recent concepts such as recovery and tend to focus mostly on medication, chronicity, and symptoms. During a recent trial on CBT for early psychosis, many family members asked to learn more about CBT for psychosis and how they could use the tools in their lives. We therefore developed the family psychoeducation/CBT module entitled WITH (Wellness-Inform-Talk-Help) \[21\]. The module can be offered in parallel to the CBT for psychosis groups, *i.e.*, during 24, hourly multiple family sessions, or can be offered in a more intensive format: eight two-hour multiple family sessions (covering 16 activities in the module). Each multiple family group typically consists of an average of 10 parents and two co-therapists. The content of the group is psychoeducational in that it addresses concepts such as recovery, expressed emotions, parental role, personal limits, and expectations, but it is also considered CBT given that the participants learn about CBT principles and techniques and apply them to their own lives during the group and at home (homework). The parents therefore learn to not only use the skills learned with their family member with a mental illness, but also use them with themselves when they are experiencing distress for instance.

## Merging CBT and Family Psychoeducation

The intensive (eight two-hour sessions) format was recently studied in a non-controlled study \[21\] whereby the 40 parents who participated showed significant clinical improvements in psychological distress, namely in psychoticism, depression and interpersonal sensitivity compared to their baseline scores. Qualitative data obtained revealed that parents appreciated the group, found it helpful, and they had integrated recovery as well as CBT notions and skills in order to improve their relationship with their family member receiving psychiatric services. The group format was especially appreciated, as well as the information covered in the module. Although more studies are warranted in order to compare the WITH multiple family intervention to other family interventions, social workers offering the group anecdotally mentioned that their previous multiple family psychoeducational intervention had a retention rate of only 20% of participants from the first to the last session whereas WITH had a retention rate of 80%. The merged intervention has the advantage of covering essential elements of family psychoeducation for psychosis, including updated information on recovery, and also offers concrete CBT tools that can be useful for the person with a mental illness as well for their family members.

# 4. Supported Employment and Other Evidence-Based Interventions

Supported employment is another evidence-based program that has attracted a few merges over the past decade. Supported employment programs help people with severe mental illness obtain real-world competitive employment, with regular wages, based on their clients' preferences \[6\]. Employment specialists working in supported employment programs aim at quickly finding regular paid work for their clients, and offer them unlimited support according to their needs at work. Supported employment programs are recognized as being evidence-based with more than 15 trials in various countries having demonstrated that SE programs are more efficacious in helping people with severe mental illness obtain regular jobs than other vocational or rehabilitation programs \[6\]. Nonetheless, there is room for improvement given that on average, in North America, between 40%–60% of the clients in SE programs obtain regular jobs and most jobs are only kept for three to five months. Many reasons have been suggested to explain why some individuals might struggle in finding work or in maintaining their jobs. Some have suggested lack of appropriate work-related social skills, others that cognitive deficits impede on work performance, and others still that people with mental health problems might hold irrational beliefs about themselves and the workplace.

## Merging Social Skills Training and Supported Employment Programs

The first merge proposed was to offer social skills training that was work specific to people registered in a supported employment program. Charles Wallace \[24\] developed the *Workplace Fundamentals*, aiming at helping participants recognize the advantages of work in their lives, their potential stressors at work, how to problem solve various work-related situations, and how to avoid drugs and alcohol to maintain their jobs. The module is offered over the course of 24 sessions, typically twice a week, in groups of six to eight participants. As with most social skills training, the goal is to develop spontaneous behaviors and therefore involves multiple role-plays and repetitive behaviors. Two studies were conducted to verify its efficacy in improving job tenure. The first, including 34 participants, showed improved job tenure and better work satisfaction for those having received the skills training + SE program compared to SE program alone \[24\], whereas the second study did not show any differences between the two conditions on work outcomes (but reported that the sample was not typical of most studies with higher education and longer tenure, with rates close to one year for their first job) \[25\]. The participants receiving both conditions did show greater knowledge regarding their work setting, stressors and showed better problem solving abilities than those receiving only the SE program.

# 5. Cognitive Remediation and Supported Employment

Another explanation for poor work tenure in people receiving SE programs pertains to cognitive deficits. Cognitive deficits are well documented in people with severe mental illness, namely regarding deficits in memory, attention, speed of processing and various executive functioning tasks, and can make performing at work difficult. Various cognitive remediation programs and strategies have been developed over the years with more than 40 randomized controlled trials supporting its efficacy in improving cognitive skills and overall functioning \[26\]. Cognitive remediation can take many forms: paper-pencil tasks, computer tasks, group training, or training in real-world tasks (using errorless learning, for instance \[27\]). Although some cognitive remediation can include modifying the environment to compensate for the person's most important cognitive deficit, most cognitive remediation programs aim at improving cognitive deficits to the point that they no longer interfere with work performance.

## Merging Cognitive Remediation and Supported Employment Programs

McGurk and colleagues developed a cognitive remediation program called *Thinking Skills for Work* specifically for people registered in supported employment programs \[28\]. The program involves individual computerized training (using CogPack) for an average of 24 hours over the course of 12 weeks, along with cognitively-informed job support consultation with the employment specialist. The computerized program aims at improving attention, concentration, psychomotor speed, learning and memory as well as executive functions. The consultation aims at targeting jobs or at modifying the work environment as needed according to the person's performance and progress during the cognitive remediation training. Results at the two to three year post- cognitive remediation follow-ups revealed that those who had received the cognitive remediation program had improved on the cognitive tasks and had superior job retention rates than the control condition (registered in supported employment programs only) \[29\]. These results were however not found for those who presented with comorbid substance use disorders—their work outcomes were poor regardless of the extra treatment added \[30\].

# 6. CBT and Supported Employment

A potential obstacle to job maintenance in people registered in supported employment is dysfunctional beliefs regarding the workplace and one's own abilities. Individuals with severe mental illness who have been away from the job market for some time can hold beliefs and act in ways that are deleterious for their work integration, and could be influenced by lack of confidence, jumping to conclusions bias, and poor coping skills, to name a few. As mentioned previously, CBT has proven efficacious in modifying beliefs and cognitive biases and helps in developing better coping strategies when dealing with stressful situations. CBT has also been modified by Davis and colleagues \[31\] to target work beliefs and behaviours in a transitional vocational program for veterans with severe mental illness. This program, entitled IVIP, has demonstrated improvements in work performance and job maintenance in those receiving the group IVIP compared to those participating in the vocational program alone \[32\]. These results were also replicated in a larger trial \[33\].

## Merging CBT and Supported Employment Programs

Lecomte, Corbière, Titone and Lysaker \[34\] developed a brief CBT group intervention, inspired by the IVIP, but specifically tailored for people in supported employment programs called CBT-SE. The CBT-SE intervention is offered during 8 sessions over the course of one month, in order to ensure that the group does not impede on the rapid job search principle of supported employment programs. The content covered many essential aspects linked to the workplace, such as recognizing and managing one's stressors at work, determining and modifying dysfunctional thoughts (e.g., not jumping to conclusions, finding alternatives, seeking facts), overcoming obstacles (e.g., problem solving), improving one's self-esteem as a worker recognizing strengths and qualities), dealing with criticism, using positive assertiveness, finding coping strategies (for symptoms and stress) to use at work, negotiating work accommodations and overcoming stigma. Although the results from the trial of 160 participants are not yet available, preliminary data have been published on 24 participants \[35\] and suggest that the CBT-SE intervention is feasible, and acceptable, with good attendance and positive feedback regarding the group's usefulness. In terms of work outcomes, 50% of all participants in both conditions found competitive work but those in the CBT-SE condition were more likely to work more hours per week and for more consecutive weeks than those in the supported employment program alone. These preliminary results are promising, although results from the full trial are needed before concluding that CBT-SE is efficacious in improving job tenure.

# 7. Conclusions

Evidence-based psychosocial practices for individuals with severe mental illness can greatly improve people's lives but are unfortunately scarcely implemented. When large-scale governmental or agency supported implementation initiatives are not available, clinical or community settings who are tempted to offer one evidence-based program or intervention could also opt for a merged intervention. Merged interventions have the advantage of targeting two sets of skills at once, and could therefore generalize in other aspects of the person's life. For instance, individuals having received cognitive remediation within a supported employment program \[28\] could see improvements in other areas of their lives, outside of work, from their improved memory and attention skills. Similarly, the cognitive behavioural strategies used in the CBT-SE skills \[34\] are similar to those used in more general CBT for psychosis treatments and could be used to help the person assess situations differently at work as well as outside of work, with friends or family for instance.

This article aimed at presenting some merges of evidence-based programs but is in no way exhaustive. Other merges exist, such as social skills training with token economy for substance misuse \[36\] cognitive remediation with social skills training (e.g., Integrated Psychological Therapy - IPT \[37\]) or social cognitive training with CBT and skills training (*i.e.*, Social Cognition and Interaction Training—SCIT \[38\]). These programs are however described as distinct and unique programs, not as merges of evidence-based interventions. Although evidence-based interventions are empirically supported, their impact on various outcomes can likely be improved by adding elements from other evidence-based interventions, or by offering them within an evidence-based program, as was demonstrated here. Although some of the proposed merged interventions have only been studied in small or uncontrolled studies so far, the strong empirical support for the non-merged evidence-based interventions from which they are derived and the preliminary data available so far is quite encouraging. Future studies on merged evidence-based interventions are warranted, particularly in terms of trials assessing the effectiveness of offering such interventions simultaneously rather than separately and at different times. Furthermore, studies should also consider measuring the level of integration of the practices in order to determine if closely-knit merges are more effective than less integrated practices. Finally, studies should also investigate if these merges increase or not generalization of the skills to other life domains.

## Author Contributions

The authors contributed equally to this work.

## Conflicts of Interest

The authors declare no conflict of interest.

# References

[^1]: These authors contributed equally to this work.


abstract: # Background
  .
  Dietary assessment tools are often too long, difficult to quantify, expensive to process, and largely used for research purposes. A rapid and accurate assessment of dietary fat intake is critically important in clinical decision-making regarding dietary advice for coronary risk reduction. We assessed the validity of the MEDFICTS (MF) questionnaire, a brief instrument developed to assess fat intake according to the American Heart Association (AHA) dietary "steps".
  .
  # Methods
  .
  We surveyed 164 active-duty US Army personnel without known coronary artery disease at their intake interview for a primary prevention cardiac intervention trial using the Block food frequency (FFQ) and MF questionnaires. Both surveys were completed on the same intake visit and independently scored. Correlations between each tools' assessment of fat intake, the agreement in AHA step categorization of dietary quality with each tool, and the test characteristics of the MF using the FFQ as the gold standard were assessed.
  .
  # Results
  .
  Subjects consumed a mean of 36.0 ± 13.0% of their total calories as fat, which included saturated fat consumption of 13.0 ± 0.4%. The majority of subjects (125/164; 76.2%) had a high fat (worse than AHA Step 1) diet. There were significant correlations between the MF and the FFQ for the intake of total fat (r = 0.52, P \< 0.0001) and saturated fat (r = 0.52, P \< 0.0001). Despite these modest correlations, the currently recommended MF cutpoints correctly identified only 29 of 125 (23.3%) high fat (worse than AHA Step 1) diets. Overall agreement for the AHA diet step between the FFQ and MF (using the previously proposed MF score cutoffs of 0–39 \[AHA Step 2\], 40–70 \[Step 1\], and \>70 \[high fat diet\]) was negligible (kappa statistic = 0.036). The MF was accurate at the extremes of fat intake, but could not reliably identify the 3 AHA dietary classifications. Alternative MF cutpoints of \<30 (Step 2), 30–50 (Step 1), and \>50 (high fat diet) were highly sensitive (96%), but had low specificity (46%) for a high fat diet. ROC curve analysis identified that a MF score cutoff of 38 provided optimal sensitivity 75% and specificity 72%, and had modest agreement (kappa = 0.39, P \< 0.001) with the FFQ for the identification of subjects with a high fat diet.
  .
  # Conclusions
  .
  The MEDFICTS questionnaire is most suitable as a tool to identify high fat diets, rather than discriminate AHA Step 1 and Step 2 diets. Currently recommended MEDFICTS cutpoints are too high, leading to overestimation of dietary quality. A cutpoint of 38 appears to be providing optimal identification of patients who do not meet AHA dietary guidelines for fat intake.
author: Allen J Taylor; Henry Wong; Karen Wish; Jon Carrow; Debulon Bell; Jody Bindeman; Tammy Watkins; Trudy Lehmann; Saroj Bhattarai; Patrick G O'Malley
date: 2003
institute: 1Cardiology Service, Walter Reed Army Medical Center, Washington, DC, USA; 2Dwight D. Eisenhower Army Medical Center, Ft. Gordon, GA, USA; 3General Internal Medicine Service, Walter Reed Army Medical Center, Washington, DC, USA; 4Systems Assessment & Research, Inc., Lanham, MD, USA
references:
title: Validation of the MEDFICTS dietary questionnaire: A clinical tool to assess adherence to American Heart Association dietary fat intake guidelines

# Background

Dietary fat intake is a risk factor for coronary heart disease and the modification of dietary habits is important for the prevention of cardiovascular disease. The assessment of dietary fat intake is a critically important first step in clinical decision-making regarding dietary and pharmacotherapeutic advice on coronary risk reduction. Thus, a rapid and accurate tool to assess dietary fat intake would be a clinically useful screening tool for physicians to counsel patients about diet and coronary risk reduction.

Commonly used dietary assessment tools include dietary history, 24-hour recall, seven-day recall, seven-day record, and food frequency questionnaire. \[1-7\] Impediments to more widespread clinical use of these tools include their length, and the difficulty and expense of their analysis. Furthermore, nutrition researchers tend to focus on a method's ability to yield precise and accurate measurement of a nutrient rather than to evaluate whether a tool can simply and quickly identify an individual's distribution or pattern of food intake. We compared the accuracy of the MEDFICTS (MF) questionnaire,\[8\] a brief instrument developed to assess fat intake according to the American Heart Association (AHA) dietary "steps,"\[9,10\] to the standardized Block Food Frequency Questionnaire\[11,12\] (FFQ) in a sample of active duty US Army personnel without known coronary artery disease.

# Methods

## Subjects

This study contains data from 164 active-duty U.S. Army personnel who completed both the MF and Block FFQ. Subjects completed the surveys during the same intake interview for a primary prevention intervention trial – the Prospective Army Coronary Calcium (PACC) Study. The study was approved by the Department of Clinical Investigation of the Walter Reed Army Medical Center.

The methods of the PACC Study have been previously described.\[13\] Briefly, since October 1998, active-duty Army personnel from 39 through 45 of age who were stationed in the National Capital Area of the Walter Reed Health Care System were recruited at the time of a periodic, Army-mandated physical examination. Persons who had a history of coronary heart disease or who reported a history of angina pectoris on the Rose questionnaire were ineligible. Between October 26, 1998 and November 4, 1999, 705 eligible participants were screened and 630 provided written informed consent to undergo electron beam computed tomography (EBCT) in addition to the required physical examination procedures. A subset of these subjects also volunteered to participate in a randomized, controlled trial to assess the impact of the knowledge of EBCT results and nurse-based case management on risk factor modification. The 164 subjects included in this dietary assessment study are a consecutive sample of subjects who both consented to participate in the randomized controlled trial and who also completed the MF and Block FFQ questionnaires. Demographic characteristics of the study participants are shown in Table 1.

Demographic Characteristics and Select Cardiac Risk Factors of the PACC Participants (N = 164)

| **Variable**                 | **Value\*** |
|------------------------------|-------------|
| Demographic Characteristics: |             |
|  Male gender (%)             | 79.9        |
|  Age (yr)                    | 42 ± 2      |
|  Caucasian (%)               | 65.9        |
|  College educated (%)        | 78.4        |
| Cardiac Risk Factors:        |             |
|  Total cholesterol (mg/dl)   | 203 ± 34    |
|  LDL (mg/dl)                 | 130 ± 33    |
|  HDL (mg/dl)                 | 52 ± 14     |
|  Triglycerides (mg/dl)       | 117 ± 64    |
|  BMI                         | 27 ± 4      |
|  Waist girth (cm)            | 92 ± 10     |

\*Plus-minus values are means and standard deviations.

## Dietary Assessment Tools

Each participant filled out a series of questionnaires that included the 2 dietary assessment tools: the validated and reduced version of the Block FFQ and the full version of the MF. The reduced version of Block FFQ is a validated food survey that contains 60 food items and is intended to capture all nutrients in the diet including dietary fat intake. The survey requires approximately 15 minutes to self-administer, however, the survey requires a relatively detailed analysis, thus the results are not immediately available for patient counseling. This study focuses only on those variables from the Block FFQ that are relevant to dietary fat intake within the dietary guidelines of the American Heart Association (AHA). This includes total calories, percentage of calories from fat and saturated fat, and cholesterol intake.

The MF questionnaire was specifically designed to evaluate patient adherence to the National Cholesterol Education Program (NCEP) Step 1 and Step 2 diets adopted by the American Heart Association (AHA). The main objective of these dietary steps is incrementally reduce coronary heart disease risk through diet-induced reduction in LDL cholesterol. Both the AHA Step 1 and 2 diets focus on reducing total fat to 30% or less of daily energy, and progressively reducing saturated fat and cholesterol intake (Step 1: 7–10% of energy from saturated fat and \<300 mg cholesterol; Step 2: \<7% of energy from saturated fat and \<200 mg cholesterol). The AHA Step 1 diet is recommended for all healthy persons for the prevention of coronary heart disease, and is recommended to precede pharmacotherapy of LDL cholesterol. The Step 2 diet is recommended to further reduce LDL cholesterol for patients that have already achieved their Step 1 dietary goals. Additionally, the Step 2 diet is the initially recommended diet for patients with either a high-risk cholesterol level (\>240 mg/dL) or with known coronary heart disease.

The MEDFICTS questionnaire is a brief instrument consisting of 8 food categories: **M**eats, **E**ggs, **D**airy, **F**ried foods, fat **I**n baked goods, **C**onvenience foods, fats added at the **T**able, and **S**nacks. The first column of the questionnaire addresses each of these food categories. Within each category, food items are assigned to either group 1 (desirable) or group 2 (undesirable) based upon total fat content. Numeric values are assigned to each food group, with weightings based upon weekly consumption and serving size. The questionnaire is scored using totaling the quality-adjusted intake quantity yielding a possible range of scores from 0 to 216 points. Lower MF scores indicate diets containing less dietary fat. Prior validation literature indicated that a score of \<40 points is consistent with a Step 2 diet, a score between 40 to 69 is consistent with a Step 1 diet, and a score of \>70 is considered as high fat diet. The MF can be self-administered in 3 to 5 minutes, and scored by the healthcare provider in approximately 2 minutes. Thus, the MF is an efficient tool enabling health care providers to quickly assess the adherence of patients to the fat components of a Step 1 or 2 diet, and identify patients consuming a diet higher in total fat, saturated fat, and cholesterol.

## Statistical Analysis

The two dietary questionnaires were independently scored. The reduced version Block FFQ was coded and analyzed by the same investigator to provide consistency in scoring. The validation of MF scores with Block FFQ dietary variables (percent of fat, percentage of saturated fat, and cholesterol level) was evaluated by Spearman's rho, because both dietary scores were not normally distributed. The level of inter-test agreement between the two dietary instruments was assessed using the kappa statistic. Receiver operating characteristic (ROC) Curve analysis was applied to measure the sensitivity and specificity of the alternative MF cutpoints. All analyses were performed using SPSS for Windows (v 10.05, Chicago, IL). Data are presented as mean ± SD. A two-tailed P value of ≤ 0.05 was considered to indicate statistical significance.

# Results

Mean daily intake values included total fat (% calories) of 35.5 ± 13.0%, saturated fat 13.0 ± 0.4%, and cholesterol 267 ± 283 mg/dL. These data, obtained with the Block FFQ, indicated that 76.2% of the participants had a high fat (worse than the AHA Step 1) diet. In contrast, the MF questionnaire identified only 17.7% of the group as having a high fat diet (Table 2). The other subjects (82.3%) were indicated as having a low fat diet, and were approximately equally divided between AHA Step 1 and 2 diets.

Dietary data for the study group

| **Dietary Data** | **Male (N = 131)** | **Female (N = 33)** | **Total (N = 164)** |
|----|----|----|----|
| MEDFICTS Data: |  |  |  |
|  Diet Group Distribution (%)\* |  |  |  |
|   High fat diet | 19.8 | 9.1 | 17.7 |
|   Step 1 diet | 44.3 | 39.4 | 43.3 |
|   Step 2 diet | 35.9 | 51.5 | 39.0 |
|  Total MEDFICTS Score | 49 ± 27\*\* | 41 ± 27 | 48 ± 27 |
| Block Dietary Data: |  |  |  |
|  Total Calories | 1576 ± 674 | 1321 ± 530 | 1525 ± 654 |
|  % fat | 35.8 ± 14.0 | 34.4 ± 1.0 | 35.5 ± 13.0 |
|  % saturated fat | 12.7 ± 0.4 | 12.2 ± 0.4 | 12.6 ± 0.4 |
|  Cholesterol (mg/dl) | 283 ± 311 | 201 ± 98 | 267 ± 283 |

\* MEDFICTS Diet Groups: High fat diet group: MEDFICTS score \>70 Step 1 diet group: MEDFICTS score: 40–70 \<30% fat, \<10% saturated fat, \<300 mg/dl cholesterol Step 2 diet group: MEDFICTS score \<40 \<30% fat, \<7% saturated fat, \<200 mg/dl cholesterol Data shown are means ± standard deviations.

There were significant correlations between the MF and Block FFQ for the percentage intake of fat (r = 0.52, P \< 0.0001), saturated fat (r = 0.52, P \< 0.0001), and cholesterol (r = 0.55, P \< 0.0001). Subjects within the different MF diet categories did significantly differ with respect to fat intake (Table 3). Despite these modest correlations, the MF (based on the currently-recommended MF score cutoffs of 0–39 for Step 2, 40–70 for Step 1, and \>70 for high fat diets) correctly identified only 29 of 125 (23.3%) high fat (worse than AHA Step 1) diets, and 19.2% of Step 1 diets (Table 4). The overall agreement for the AHA diet steps between the Block FFQ and MF was negligible (kappa statistics = 0.036). The MF was accurate at the extremes of fat intake, but could not reliably separate patient groups into 3 AHA dietary classifications.

Comparisons of daily caloric, fat and cholesterol intake within MEDFICTS Diet Groups

| **Block Dietary** | **High Fat** | **Step 1** | **Step 2** | **ANOVA** |          |
|-------------------|--------------|------------|------------|-----------|----------|
| **Variable**      | **Diet**     | **Diet**   | **Diet**   | **F**     | **Sig.** |
| Total calories    | 1980         | 1540       | 1302       | 12.3      | .0001    |
| % fat             | 40.9         | 38         | 30.3       | 10.1      | .0001    |
| % saturated fat   | 15.7         | 13.1       | 10.6       | 22.1      | .0001    |
| Cholesterol       | 351          | 309        | 181        | 5.3       | .006     |

MEDFICTS Diet Groups and AHA Diet Steps Crosstabulation

| **MEDFICTS Diet Groups** | **AHA Diet Steps** |  |  |  |
|----|----|----|----|----|
|  | **High Fat** | **Step 1** | **Step 2** | **Total** |
| High Fat Diet | 29 (100.0%)\* (23.2%)\*\* |  |  | 29 (100.0%) (17.7%) |
| Step 1 Diet | 62 (87.3%) (49.6%) | 5 (7.0%) (19.2%) | 4 (5.6%) (30.8%) | 71 (100.0%) (43.3%) |
| Step 2 Diet | 34 (53.1%) (27.2%) | 21 (32.8%) (80.8%) | 9 (14.1%) (69.2%) | 64 (100.0%) (39.0%) |
| Total | 125 (76.2%) (100.0%) | 26 (15.9%) (100.0%) | 13 (7.9%) (100.0%) | 164 (100.0%) (100.0%) |

\* % within MEDFICTS diet groups. \*\* % within AHA diet steps.

Exploratory analysis showed that alternative MF cutpoints of \<30 (Step 2), 30–50 (Step 1), and \>50 (high fat diet) were highly sensitive (96%), but had low specificity (46%) for a high fat diet. Receiver operating characteristic (ROC) curve analysis showed that a single MF score cutoff of 38 yielded optimal sensitivity of 75% and specificity of 72% (Figure 1), and had modest agreement (kappa statistics = 0.39, P \< 0.001) with the Block FFQ for the identification of patients with a high fat diet (Figure).

# Discussion

The effective identification of patients requiring dietary intervention for the reduction of fat intake requires an accurate, efficient, clinically applicable dietary assessment tool. In this study, we compared the accuracy of the MEDFICTS dietary survey to the Block FFQ for the identification of compliance with the AHA dietary guidelines for fat intake. These data indicate that the MF questionnaire has moderate accuracy for the semi-quantitation of dietary fat and saturated fat intake. However, the currently-recommended MF cutpoints resulted in marked over-estimation of dietary quality, including an inability to accurately detect high fat diets. Furthermore, this tool does not appear to have adequate test characteristics to accurately discriminate Step 1 and Step 2 diets. This is likely due to the small differences in fat intake between these 2 diets, and the relatively crude nature of the MF survey. However, our data suggest that a revised cutpoint of 38 for the MF questionnaire resulted in modest accuracy for the detection of a high fat diet.

Beyond ease of administration, an additional advantage of the MF survey may be its utility as a tool for dietary education and lifestyle modification. The content and design of the MF is clear and simple, but comprehensive enough to categorically provide dietary fat intake guidance for a wide variety of food goods. The survey provides rapid depiction of the greatest contributors to dietary fat intake within a given patient's diet, and suggests strategies (alternative food choices, or reduced portion size) for the reduction of dietary fat. However, whether the MF would serve as a useful tool to guide dietary modification will require further study.

# Conclusions

The MF questionnaire is an efficient tool that can be used by health professionals to quickly assess the dietary fat intake. It provides immediate identification of patients consuming a diet higher in total fat, saturated fat, and cholesterol than currently recommended by the American Heart Association. However, the current recommended cutpoints of the MEDFICTS questionnaire are unable to discriminate the AHA Step 1 and Step 2 diets. Current MEDFICTS cutpoints are too high, leading to overestimation of dietary quality. A cutpoint of 38 appears to be providing optimal identification of patients who do not meet AHA dietary guidelines for fat intake.

Allen J. Taylor- Project design, data analysis, manuscript preparation Henry Wong- Project design, data analysis, manuscript preparation Karen Wish- Primary data analysis, manuscript preparation Jon Carrow- Data collection, data analysis, manuscript preparation Debulon Bell- Data collection, data analysis, manuscript preparation Jody Bindeman- Data collection, data analysis, manuscript preparation Tammy Watkins- Data collection, data analysis, manuscript preparation Trudy Lehmann- Data collection, data analysis, manuscript preparation Saroj Bhattarai- Data management, data analysis, manuscript preparation Patrick G. O'Malley- Project design, data analysis, manuscript preparation


author: JE Pope; A Stevens; K McCrea; J Ouimet
date: 2004
institute: 1University of Western Ontario, London, Ontario, Canada
title: Nonsteroidal antiinflammatory drug use may be protective to cartilage in osteoarthritis of the hip and knee

# Purpose

Nonsteroidal antiinflammatory drugs (NSAIDs) are used to alleviate osteoarthritis (OA) symptoms and are not considered disease-modifying. We studied NSAID use in subjects with hip or knee OA to investigate the relationship between NSAIDs and OA severity.

# Methods

Subjects (seen over 2 years at teaching hospitals in London, Ontario) were referred to orthopedic surgeons or rheumatologists, had radiographs available, but had no inflammatory arthritis or evidence of secondary OA. Subjects were divided into mild, moderate (mod) and severe OA by X-ray (worst joint selected). A questionnaire was mailed asking about current/ever use of specific NSAIDs (by generic and trade names) including over the counter and acetylsalicylic acid. Coxibs were not available over the study period. A total of 608 subjects were studied, having mild (71), mod (129) and severe (408) OA, with a disease duration of 10 years in each group (62% were women, who had proportionately more mild disease than men).

# Results

Those with severe versus mild OA were older (70 versus 61 years), so age was adjusted for. There was an inverse dose–response with use of \> 3 NSAIDs being used by mild versus severe OA (odds ratio 3.7), mild versus mod OA (odds ratio 2.5) and mod versus severe OA (odds ratio 1.5) (*P* \< 0.0001), and the same was found with \> 2 NSAIDs (*P* \< 0.0002); and 7% of mild, 15% of mod and 12% of severe OA had received no NSAIDs ever. Only one NSAID (ever used) was increased in severe OA (sulindac, *P* \< 0.008) compared with naproxen, tiaprofenic acid and diclofenac, more frequently used in mild than mod or severe OA (*P* \< 0.01). Other NSAID use ever was not different between the groups (including indomethacin, thought to be chondrodestructive), but numbers using indomethacin were small. Limitations may include inability to study accurately the duration of NSAID use, older age in those with severe OA (which could affect NSAID treatment choice), recall bias and unknown confounders. We did not illicit body mass index or pain level in each group.

There may be biases for referring to different specialists as the rheumatologists prescribed NSAIDs more often and surgeons treated more subjects with severe OA (*P* \< 0.0001). When analyses were stratified by specialist type, there were no differences between mild, mod and severe OA for NSAID use in subjects treated by rheumatologists; however, the trend for increased NSAID use with milder OA was evident in those seen by orthopedic surgeons. When stratified by knee and hip OA, the dose–response remained (*P* \< 0.003 and *P* \< 0.03, respectively). Subjects were followed by general practitioners, so we assumed past NSAIDs should have been prescribed equally in all groups, but this was not the case.

# Conclusions

Those with more severe OA are more rapidly progressive (having similar disease duration to the other groups) and could be innate NSAID nonresponders. However, one would assume that they should be exposed to more NSAIDs (looking for one to be helpful). We conclude that NSAID use and the number of NSAIDs used was greater in mild radiographic OA and postulate that lowering prostaglandins in the joint with NSAIDs may be protective for cartilage. Prospective studies are needed to confirm observations. Some *in vitro* models of NSAIDs in OA support our observations.


abstract: # Background
  .
  The relapsing nature and varying geographical prevalence of ulcerative colitis (UC) implicates environmental factors such as diet in its aetiology.
  .
  # Methods
  .
  In order to determine which foods might be related to disease activity in UC a new method of dietary analysis was developed and applied. Eighty-one UC patients were recruited at all stages of the disease process. Following completion of a 7 d diet diary, clinical assessment including a sigmoidoscopic examination (scale 0 (normal mucosa) to 6 (very active disease)) was conducted. Food weights for each person were adjusted (divided) by the person's calorific intake for the week. Each food consumed was given a food sigmoidoscopy score (FSS) calculated by summing the products of the (adjusted) weight of food consumed and sigmoidoscopy score for each patient and occurrence of food and dividing by the total (adjusted) weight of the food consumed by all 81 patients. Thus, foods eaten in large quantities by patients with very active disease have high FSSs and vice versa. Foods consumed by \<10 people or weighing \<1 kg for the whole group were excluded, leaving 75 foods.
  .
  # Results
  .
  High FSS foods were characterized by high levels of the anti-thiamin additive sulfite (Mann-Whitney, p \< 0.001), i.e. bitter, white wine, burgers, soft drinks from concentrates, sausages, lager and red wine. Caffeine also has anti-thiamin properties and decaffeinated coffee was associated with a better clinical state than the caffeine containing version. Beneficial foods (average intake per week) included pork (210 g), breakfast cereals (200 g), lettuce (110 g), apples and pears (390 g), milk (1250 ml), melon (350 g), bananas (350 g), bacon (120 g), beef and beef products (500 g), tomatoes (240 g), soup (700 g), citrus fruits (300 g), fish (290 g), yogurt (410 g), cheese (110 g), potatoes (710 g) and legumes (120 g).
  .
  # Conclusions
  .
  The dietary analysis method described provides a new tool for establishing relationships between diet and disease and indicates a potentially therapeutic diet for UC.
author: Elizabeth A Magee; Laurie M Edmond; Shiona M Tasker; San Choon Kong; Richard Curno; John H Cummings
date: 2005
institute: 1Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, UK
references:
title: Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis

# Background

Ulcerative colitis (UC) is a chronic, relapsing mucosal disorder that extends in continuous fashion proximally from the rectum and is limited to the colon. The aetiology of UC includes a genetic component possibly involving an abnormal cell-mediated immune response to commensal enteric bacteria in the large intestine. The relapse/remission pattern of the disorder and substrate driven nature of microbial metabolism in the large bowel implicate environmental factors such as diet.

Apart from nutritional repletion, dietary measures do not play a role in the management of UC. Nonetheless, attempts to link the cause of UC with specific foods date back at least 50 years\[1\]. Many foods or food groups have been related to UC (table 1 – see additional file 1) \[2-13\] including sugar, eggs, soft drinks, fruit and vegetables, protein, carbohydrate and fat. However none have been proven to be of significant benefit or to contribute to the cause of UC. This may partly be because both the assessment of disease activity in UC and dietary intake are difficult to measure, or because the actual dietary component that is key to this relationship has not been measured.

It has been proposed that sulfide, produced in the large bowel from either amino acid fermentation or sulfate reduction, may be a triggering factor in the inflammatory process of UC \[14-16\]. Recently, in a prospective dietary study where foods rich in sulfur compounds were quantitated, evidence that sulfur compounds may increase the likelihood of subsequent relapse in UC was found\[17\].

The main source of inorganic sulfur, predominantly sulfate, in the diet are the S (IV) family of additives; the sulfiting agents. Sulfites have been used as food preservatives since the 17th century and are amongst the most widely accepted and versatile of additives. Sulfiting agents, denoted by E220–228 in Europe and generally recognized as safe (GRAS) substances in the USA, include sulfur dioxide, hydrogen sulfites, sulfites and metabisulfites. Sulfiting agents are cheap, easy to use and extremely effective at preventing microbial growth and reducing spoilage\[18\]. They serve as antioxidants, inhibit enzymatic and non-enzymatic browning reactions and act as a texture modifier in biscuit dough. Sulfites improve color extraction from, and stabilization of grape must in winemaking and preserve lobsters and shrimps from discoloration during iced storage.

However, there are some problems with sulfite use\[19,20\]. In the early 1980s ingestion or inhalation of sulfites was shown to cause bronchospasm in about 5 % of asthmatics. Sulfite sensitivity can pose a particular threat in the workplace where sulfiting agents are used, but may also occur with ingestion of sulfited foods such as potato products and wine. In addition, skin sensitivity has been reported and there are anti-nutritional effects particularly to thiamin which is readily cleaved by the sulfite ion\[21\]. The mechanism involves an initial nucleophilic attack to the methylene carbon activated by the positive charge on nitrogen, the reaction rate peaking between pH 5 and 6\[18\]. As a result of this anti-nutritional effect the GRAS status for sulfites was reviewed in the USA and in 1986 the use of sulfites in fresh and frozen fruit and vegetables revoked and a declaration on the label required\[22,23\]. Earlier (in the USA) their use in meat had been prohibited, because these foods are an important source of thiamin.

A study of diet and disease activity in UC using a 7 d dietary diary, a full assessment of disease activity and a method of dietary data analysis that allows trends in food consumption not apparent using customary dietary software was therefore undertaken.

# Methods

## Subjects

Eighty-one UC patients were recruited and informed consent obtained. Ethical permission was granted by Tayside Committee on Medical Ethics, Dundee, UK (ref 007/00). As it was important to have a range of disease activities present, recruitment included patients at all stages of the disease. Patients were excluded if clinical examination or histology indicated Crohn's disease or indeterminate colitis, if there was a positive stool culture for pathogens or if the patient had antibiotic treatment within 3 months preceding the start of the study.

## Dietary Assessment

All the UC patients were asked to complete a 7 d diet diary\[24\]. The diet diary used has been validated for use in the European Prospective Investigation into Cancer study (EPIC). Following completion of the diet diary, subjects attended the research clinic and a full clinical assessment (see below) was carried out. The time interval between the first day of the diary and the clinical visit was on average 28 d. Thus the dietary data is prospective.

7d diet diaries were coded and analyzed using Tinuviel, WISP v3.0 nutritional analysis software (Warrington, UK). Due to the variation in the sulfiting protocols and widespread use of sulfiting agents, current tables of food composition do not contain inorganic sulfur values and cannot be used to quantify intake. Instead of quantitating the intake of particular dietary components, foods and food groups were assessed in their entirety using the method described in the dietary data analysis section (below).

## Clinical Assessment

Clinical assessment included history, physical examination and global clinical grading, plus full blood count, liver function tests and inflammatory markers. Patients were examined by rigid sigmoidoscopy or flexisigmoidoscopy and graded on a scale 0–6 (integers and half integers used) according to the macroscopic appearances of the rectal mucosa at a distance 5–10 cm from the anal verge\[25\]. The clinical assessment of disease activity was confirmed in each case by histological examination, by a single histopathologist blinded to the clinical details, of a rectal biopsy taken from the posterior rectal wall 5–10 cm from the anal verge\[26\]. A simple clinical colitis score was assigned to patients on each visit following Walmsley's scoring system\[27\], together with blood parameters of disease severity (Hb, plasma viscosity, CRP, serum albumin).

## Dietary Data Analysis

Patterns of dietary intake associated with disease activity became apparent through the study of the dietary diaries, e.g. high intakes of sulfite containing foods coupled with a modern processed, convenience diet was associated with a high sigmoidoscopy score. Traditional dietary coding (WISP) did not show any such clear associations between micro or macro nutrient intake and sigmoidoscopy score. Traditional dietary analysis was therefore thought to be missing important patterns in dietary data and a new method of dietary assessment was subsequently developed.

This new method used the following procedure. To calculate the association of a particular food with clinical score, each food or food group consumed was given a food sigmoidoscopy score (FSS) calculated by summing the products of food weight and sigmoidoscopy score for each occurrence of the food or food group and dividing by the total weight of the food or food group contained in all diaries. In order for each diary to make equal contributions to the FSSs, the weight of each food was adjusted using the calorific intake for each person. This procedure was carried out separately for every food item recorded in the 7 d diet diaries but is explained below using the example of red wine.

Red wine score = (Σv(i)s(i))/Σv(i) for i = 1 to 81     equation 1.

Where: -

i is the 7 d dietary diary number (n = 81).

v(i) is the volume (divided by calorific intake for patient (i) of red wine recorded in 7 d dietary diary i.

s(i) is the sigmoidoscopy score associated with 7 d dietary diary (i).

Thus foods eaten in large quantities by patients with high levels of disease activity will have high scores and vice versa. The denominator in the above equation is the total volume of the food in question from all diaries (corrected for calorific intakes) so the food scores can be equated with the effect of a typical portion of the food in question on the sigmoidoscopy scores of the patients. This procedure is repeated for every food item. Foods or food groups were excluded from the analysis if 10 or fewer people consumed them or if they made up less than 1 kg of the total intake of the entire population. The decision as to where food group boundaries lay was made depending on the size of the group and whether the differences between the foods were considered important for this study.

## Statistics and Data Handling

Dietary data was exported from WISP to Microsoft EXCEL 98 (Macintosh version, 1998). A worksheet containing the core headings; Patient ID, food description, weight and patient sigmoidoscopy score was completed. The data was then sorted by food description and each food copied to a separate EXCEL file. Equation 1 was then used to calculate food sigmoidoscopy scores for each food in a manner similar to the example in table 2 (see additional file 2).

Correlation values for scatter plots were obtained using the linear regression function in EXCEL. The equation t = r √((n-2)/(1-r^2^)) combined with t tables provided corresponding significance levels.

# Results

Of the 81 patients recruited 43 were male and 38 female. The average age (range) of the males and females were respectively 53 (26–78) y and 47 (19–74). The distribution of sigmoidoscopy scores is shown in fig 1. One third of the patients had sigmoidoscopy scores of 0, 0.5 or 1. The mean sigmoidoscopy score for all 81 patients was 2.09. The correlation between the clinical activity indexes and sigmoidoscopy scores was r^2^ = 0.25 (n = 81).

Table 3 (see Additional file 3) shows the foods and food groups with associated sigmoidoscopy scores and average portion sizes. In total 75 foods (or food groups) were given FSS scores. The higher the FSS value the greater the association with disease activity and vice versa. The total weight of foods in all diaries was 1,681 kg. The average food sigmoidoscopy score (i.e. a food sigmoidoscopy score calculated for the entire dietary intake data set was 2.127). Foods excluded from the FSS table (Table 3), by virtue of contributing \<1 kg or being consumed by \<10 people, made up 8 % of the total weight of all foods and had a score slightly lower (2.001) than that of an average food (2.127). Standard errors are not quoted for the food scores as the data used to generate them (weight \* sigmoidoscopy score) was not normally distributed due to the number of sigmoidoscopy scores of 0.

The dietary diaries were assessed for completeness by comparing calorific intakes with expected values for the sexes. Expected (calculated from dietary reference tables using age and sex)\[28\] versus actual values for men and women were respectively 2481 kcal/d versus 2326 kcal/d and 1925 kcal/d versus 1887 kcal/d.

Foods for which regulations exist in the EU permitting sulfite addition are shown in table 4 (see Additional file 4) \[29\]. Typically a manufacturer will add sulfite up to the maximum permitted level in order to achieve the longest shelf life for the product. A report on sulfite usage in the UK was produced in 2001\[30\]. Sweet wines, langoustines (prawns), dehydrated potatoes and dried fruit were not given FSS scores because their data quantity fell below the \<10 people or \<1 kg rule. Soft drinks were split into those known to contain sulfite (drinks made from fruit squash concentrates and lucozade) and the rest. In terms of intake (portion size\*sulfite concentration), for this population, the major sources of sulfite (FSS, FSS table position) were bitter beer (3.91, 75), white wine (2.87, 73), burgers (2.84, 72), soft drink concentrates (2.79, 70), sausages (2.68, 68), lager (2.47, 64) and red wine (2.00, 29). A Mann-Whitney test on the FSS positions of these foods gave a significance of p \< 0.001. The sulfite-containing, alcoholic beverages; wines and beers, were associated with increased UC disease activity, but spirits were not, which suggests a role for sulfite rather than alcohol in the disease process. A plot of alcohol consumption from wine and beer against sigmoidoscopy score revealed a significant positive correlation (n = 81, r^2^ = 0.07, p \< 0.02).

Decaffeinated coffee appeared better for the UC patient than the caffeine-containing counterpart. Decaffeinated tea is not shown on table 3 because it was only drunk by 9 people but had a FSS of 1.71 versus 2.01 for the caffeine-containing product. Whole fruit consumption appeared better than the corresponding juice (e.g. fruit juice scored 2.43 compared to citrus fruits at 1.96 and apples at 1.67).

An average thiamin concentration (mg / 100 g) for each food or food group is also shown in table 3. There is a significant correlation (p \< 0.005) between this thiamin value and the food's sigmoidoscopy score.

# Discussion

Ulcerative colitis is considered to have a genetic component. Twin studies\[31\] have shown a 10% concordance of UC in monozygotic and 3% in dizygotic twins suggesting about 90% environmental and 10% genetic contributions. The pool of genetically susceptible individuals is therefore at least 10 times greater than those diagnosed with the condition. A failure to date in identifying the gene(s) responsible points to a complicated genetic component featuring multiple polymorphisms. The first acute episode of UC must disrupt either, the ecology of, or the sensitivity and selectivity of the immune system to, the commensal enteric microflora sufficiently to cause the chronic condition. More extreme versions of the environmental conditions that lead to subsequent relapses could conceivably lead to the first acute episode.

Of all the dietary components studied in relation to UC risk and disease severity, milk has probably received the most attention. Andreson\[1\] was the first to postulate that food allergy was the cause of UC in two-thirds of his patients, and by the use of elimination diets claimed to identify the offending food and remove it. In Andreson's experience, the most common provoking antigen was cow's milk. His views were confirmed by Rowe\[32\] and later by Truelove\[33\]. They all postulated that milk protein sensitivity was an aggravating cause of disease in up to 5% of colitic patients, who benefited from a milk-free diet. While able to demonstrate circulating antibodies to milk proteins more frequently and in higher titer than in matched controls, they were unable to correlate the occurrence and titer of these antibodies with the extent, severity, or duration of colitis, or with the response to a milk-free diet. Mishkin\[34\] concluded, in a review of the subject, that IBD patients avoid dairy products to a much greater extent than the prevalence of lactose malabsorption and/or milk intolerance in this population group would justify. This observation was probably due to the incorrect perceptions of patients and arbitrary advice of physicians and authors of popular diet books.

In order to ascertain whether dietary antigens may sustain the mucosal inflammatory response, two prospective controlled trials have investigated the effectiveness of bowel rest and total parenteral nutrition as primary therapy in the management of acute UC\[35,36\]. Neither study found any benefit over conventional corticosteroid treatment alone and so the possibility of a dietary antigen driving the chronicity of the disease seems unlikely. These results are in agreement with work demonstrating\[37\] that a split ileostomy is of little benefit in the management of UC, but the latter observations may have been confounded by the development of diversion colitis\[38\].

The dietary analysis procedure proposed here has the potential to highlight trends in dietary data that would not be apparent using traditional dietary analysis software and could be useful in the study of other diseases with dietary associations. This system would highlight any possible dietary factors both positive and negative, not just sulfite. The proposed method is less reductionist than traditional coding as it assesses the risk of each food item or group rather than the risk from the foods' (quantitated) constituents. Part of the power of this study derives from the availability of a sigmoidoscopic grading (0–6) of the severity and extent of the disease. This grading provides the statistical variable that is normally obtained from a non-UC control group. Other alternative systems for analysis of disease risk for dietary components are; the use of disease occurrence odds ratios between the top and bottom quartiles of intakes, and assessing the correlation coefficients between disease activity and intakes. The odds ratio method loses data and data accuracy by characterizing intakes as high, high middle, low middle and low and then discarding the middle two quartiles. The correlation method is dependent on spread. The proposed system has neither of these disadvantages. The food sigmoidoscopy score calculation does rely on the assumption that the sigmoidoscopy score is an approximately linear scale, i.e. a sigmoidoscopy score of 6 is caused by the consumption of a double portion of a harmful food item of sigmoidoscopy score 3. This could be argued to be reasonable. Both the sigmoidoscopy grading and dietary analysis method are validated methodologies. The food sigmoidoscopy score is simply a mathematical function of these two variables. As all data is transformed according to the same simple rules any statistical treatment of the results is as valid as statistical treatment of the raw data.

Whilst clinical activity indices were used to generate analogous scores to the food sigmoidoscopy scores, the results from these measurements are not included in this paper. Clinical activity index involves subjective measurements such as a feeling of well being. Thus, the food orders generated by these measurements were not thought to be as accurate as those generated by the sigmoidoscopy scores.

The consensus of previous studies on diet and UC pointed to the modern, processed, highly refined, Western diets as being damaging. The results presented here linking diet with disease activity are broadly in agreement with this. Additionally they propose a new risk factor for UC, namely intake of sulfited foods.

The involvement of diet in UC is controversial. Differences in dietary intake between patients and controls could be a result of changes in diet brought on by the symptoms of the disease process\[4\]. While this explanation is possible it does not seem likely that patients would increase their beer and wine intake as a consequence of feeling unwell. The relationship between sulfite intake and sigmoidoscopy score in this study was extremely strong and therefore an explanation for why sulfite should be a risk factor for UC is required. Sulfite has a number of effects that may be relevant to this discussion. Sulfite may be important because it is a precursor of sulfate. Sulfate can potentially be reduced to sulfide by sulfate reducing bacteria in the colon. Sulfide is a plausible metabolic toxin in UC. Supplementing patients with sulfate decreases the microbial incorporation of hydrogen into methane (as measured by breath methane) and increases the in vitro sulfide production rate of feces\[39\]. The end metabolic product of both sulfite and protein is sulfate. Sulfate from both sources can be reduced to sulfide in the gut. The absence of a significant relationship between protein intake and disease activity in this study does not support a mechanism for UC that involves a common pathway for sulfite and protein.

Alternatively, the relevance of sulfite to UC may be because of its ability to degrade thiamin (particularly at colonic pH). Thiamin deficiency manifests itself in the nervous and cardiovascular systems. It is unlikely that it is the status of the patient that is important, but rather the amount of thiamin available to the gut microflora. An example of the importance of thiamin to the gut microflora is the requirement of the probiotic bacteria, lactobacilli, for thiamin. Thiamin status is influenced by a number of factors. Firstly, thiamin intake; in foods such as pork, fortified cereals and legumes which are good sources of thiamin, intakes were associated with improved clinical state. Traditional dietary analysis did not reveal a significant correlation between thiamin intake and sigmoidoscopy scores though no allowance is made in dietary coding software for the reduction in thiamin content caused by sulfite usage. Secondly, carbohydrate intake; Elmadfa *et al*. demonstrated that the thiamin status of adult humans depends on carbohydrate intake\[40\]. Carbohydrate (and sugar) intakes have previously been associated with UC relapse (table 1). Finally, thiamin status can be affected by caffeine's anti-thiaminergic properties. For both coffee and tea intake, the decaffeinated version was associated with better clinical state.

However, there was a sub group (n = 8) of this population who recorded an intake of either vitamin B complex or multivitamins. This sub group did not have a mean sigmoidoscopy score significantly lower that the general UC population. It is likely that vitamin B1 is a factor in the disease process but not the only nutritional one.

An additional possible interpretation for the experimentally determined food order is the carbohydrate nature and content of the foods. Carbohydrates, such as the α-amylase resistant starch (RS) and prebiotics, escape digestion in the small intestine and provide an energy substrate for the colonic microflora. Both prebiotics (found in chicory, legumes, artichokes alliums, and in small amounts in cereals) and resistant starch (potatoes, bananas, lentils and legumes) have been hypothesised to improve the colonic health of the host. For RS, resistance to digestion is a function of the morphology of the starch granules and their crystalline organisation, which is determined by the botanical source of the starch and the processing it has undergone before being eaten\[41\]. Prebiotics are non-digestible carbohydrates that selectively stimulate the growth of lactobacilli and bifidobacteria with benefit to health. Prebiotics are mainly fructose and galactose polymers with a degree polymerisation of between 2 and 60. Of the prebiotic sources; chicory and artichokes were not found in typical diets, legumes and cereals were seen to have probable benefits in this study and alliums were not. This study therefore provides only limited support for the use of prebiotics in UC. The foods containing RS were all found to be of benefit in this study and therefore the role of RS in UC is strongly supported.

Any dietary advice provided to ulcerative colitis patients should be based on the FSS table. The table is of course imperfect because of experimental error, natural variation and the associations between foods. For example, milk and cereal are coded separately but are often consumed together. Thus the magnitude of the difference in the FSSs for these two foods is less than if they'd been independent variables. Suggestions have been made in this discussion as to the factors responsible for the FSS order and to distill these factors into the advice given in Table 5 (see Additional file 5). This table is speculation, as this diet has not been formally tested in the UC population. It does however represent the only comprehensive dietary advice available to ulcerative colitis patients at this time.

The list of dietary risk factors for colon cancer\[42\] bears a similarity to the dietary risk factors presented here for UC. UC patients have an increased risk of colorectal cancer and it is probable that factors responsible for inflammation in UC patients are also responsible for neoplasia in the colon cancer population.

# Conclusion

A dietary analysis method is described that provides a new tool for establishing relationships between diet and disease. This method has been applied to the study of ulcerative colitis and points to sulfite and caffeine as being harmful, with thiamin and resistant starch being potentially therapeutic. For the first time, dietary guidelines for ulcerative colitis patients, including food portion sizes have been developed.

# Abbreviations

Ulcerative colitis (UC); Food sigmoidoscopy score (FSS); European Union (EU); Odds ratio (OD) and Confidence interval (CI).

# Competing interests

The author(s) declare that they have no competing interests.

# Authors' contributions

JHC, EAM and LME contributed to the study design and the writing of the manuscript. EAM was the co-ordinator of the study and along with ST had responsibility for managing the patients and coding the diaries. LME developed the dietary data analysis protocol assisted by RC. CK and JHC performed the sigmoidoscopic examinations of the patients. All authors read and approved the final manuscript.

# Supplementary Material

###### Additional File 1

Review of studies of diet and ulcerative colitis (UC).

Click here for file

###### Additional File 2

Food sigmoidoscopy score (FSS) calculation example for red wine (NB incomplete data set used).

Click here for file

###### Additional File 3

Foods consumed in order of food sigmoidoscopy scores (FSS)\[43\].

Click here for file

###### Additional File 4

Permitted levels of sulfite in the UK.

Click here for file

###### Additional File 5

Proposed dietary advice for ulcerative colitis patients\[44\].

Click here for file

### Acknowledgements

Core funding for this study was provided by the National Association of Colitis and Crohn's Disease. Additional funding was provided by the Sir Halley Stewart Trust, Chief Scientist Office, Scotland and the Anonymous Trust, Dundee. We are very grateful to all these organisations.

Thanks go to all those who volunteered for this study. Their enthusiasm and humour throughout the study was greatly appreciated.

Thanks go to the endoscopy staff; Shirley McLeod, Marion Winters, Shona Pryde and Sheena McWha and to our secretary Helen Cowper without whom the study would not have run so smoothly.

## Figures and Tables