The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Serum cholesterol and Suicide in first episode psychosis: A preliminary study.

BACKGROUND: Low levels of cholesterol have been described in suicide behavior including among those individuals who have an increased tendency for impulsivity. Violent suicide attempters show significantly lower cholesterol levels than nonviolent suicide attempters. The suicide rate is particularly high in the prodromal and early phase of schizophrenia. It is unclear if there is a psychopathological relationship between early psychosis, suicide, and cholesterol levels. The present study examines levels of cholesterol and suicide behavior in a cohort of early psychosis. METHODOLOGY: Sixty admitted patients with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of nonaffective schizophrenia spectrum disorder (early psychosis) were assessed in a naturalistic cross-sectional, cohort study. Psychopathology was assessed with the Positive and Negative Symptom Scale for Schizophrenia (PANSS), Hamilton Depression Rating Scale, and Scale for Impact of Suicidality-Management, Assessment and Planning of Care (SIS-MAP). Serum levels of cholesterol were estimated in the cohort as well. The findings were analyzed for a clinical correlation of cholesterol levels, suicidal attempters, and psychopathology. RESULTS: Out of 60 patients, 13 patients had a suicide attempt in the recent past. No serum cholesterol abnormality (3.7 ± 1.2 mmol/L) was observed in patients as a group and those with low suicidality (SIS-MAP <17, serum cholesterol: 4.1 ± 1.3 mmol/L). However, low levels of cholesterol were observed in a subgroup with severe suicidality (SIS-MAP >33; serum cholesterol: 3.5 ± 1.4 mmol/L). Females with moderate suicidality showed statistically significant lower cholesterol levels than males (P = 0.047). CONCLUSIONS: The study suggests lower levels of cholesterol in patients of psychosis with severe suicidal thoughts and depression in early psychosis. More research is required in this field to determine the neurochemistry of suicide behavior in psychosis and its significance in the prediction of suicidal behavior.

Suicide in hospitalized early psychosis patients at the time of discharge from hospital: An exploratory study of attempters and nonattempters.

BACKGROUND: Early intervention programs for psychosis are gateways for suicide prevention. These programs offer an excellent opportunity for prevention due to easy access, early identification, and provisions for continuity of care. These programs have been found effective in reducing rates of suicide after discharge to communities. The objective of this study was to examine suicide risk level among early psychosis patients admitted with and without previous suicide attempts. We hypothesized that all patients admitted with early psychosis would be at high risk of suicide, regardless of a previous suicide attempt. METHODOLOGY: Suicide risk was compared between patients admitted with a suicide attempt (n = 30) and patients admitted without a suicide attempt (n = 30). The primary outcome measure of interest was suicide risk which was measured with the Scale for Impact of Suicidality-Management, Assessment and Planning of Care clinical interview. All patients met DSM-IV TR criteria for schizophrenia. Psychopathology was assessed using the Brief Psychiatric Rating Scale and level of depression was assessed using the Hamilton Depression Rating Scale. The data were statistically analyzed. RESULTS: Patients admitted with a previous attempt (mean = 29.5, standard deviation [SD] =12.0) did not differ significantly in suicide risk from those admitted without a previous attempt (mean = 27.5, SD = 12.5), (t[58] =0.63, P = 0.53). Patients admitted without a suicide attempt scored higher in depressive symptoms (t[58] =10.62, P < 0.001) than that of admitted with a suicide attempt. There were no significant differences between patients admitted with and without suicide attempts on any comorbidity, other than a trend toward a higher prevalence of personality disorder in patients with no suicide attempt. Attempters and nonattempters did not differ on any demographic variables either. CONCLUSIONS: Of those admitted without a previous suicide attempt, our findings suggest that it is critical that all patients discharged from an acute psychiatric unit must receive comprehensive community care. The identification of risk, and subsequent intervention for suicidal and self-harm behaviors, should be a central part of treatment for all mental disorders.

Patient Information about Gout: An International Review of Existing Educational Resources.

OBJECTIVE: Inadequate patient information about gout may contribute to poor disease outcomes. We reviewed existing educational resources for gout to identify strengths and weaknesses and compare resources cross-nationally. METHODS: Content, readability, and dietary recommendations were reviewed using a sample of 30 resources (print and Web-based) from 6 countries. RESULTS: More than half of the resources were written at a highly complex level. Some content areas were lacking coverage, including comorbidity risks, uric acid target levels, and continuing allopurinol during acute attacks. CONCLUSION: Our findings suggest significant room for improvement in gout patient educational resources, particularly regarding self-management.

Multi-TI Arterial Spin Labeling MRI with Variable TR and Bolus Duration for Cerebral Blood Flow and Arterial Transit Time Mapping.

Arterial spin labeling (ASL) is an MRI perfusion imaging method from which quantitative cerebral blood flow (CBF) can be calculated. We present a multi-TI ASL method (multi-TI integrated ASL) in which variable post-labeling delays and variable TRs are used to improve the estimation of arterial transit time (ATT) and CBF while shortening the scan time by 41% compared to the conventional methods. Variable bolus widths allow for T1 and M0 estimation from raw ASL data. Multi-TI integrated pseudo-continuous ASL images were collected at 7 TI times ranging 100-4300 ms. Voxel-wise T1 and M0 maps were estimated, then CBF and ATT maps were created using the estimated T1 tissue map. All maps were consistent with physiological values reported in the literature. Based on simulations and in vivo comparisons, this method demonstrates higher CBF and ATT estimation efficiency than other ATT acquisition methods and better fit to the perfusion model. It produces CBF maps with reduced sensitivity to errors from ATT and tissue T1 variations. The estimated M0, T1, and ATT maps also have potential clinical utility. The method requires a single scan acquired within a clinically acceptable scan time (under 6 minutes) and with low sensitivity to motion.

Pathways to psychosis in cannabis abuse.

Cannabis has been implicated as a risk factor for the development of schizophrenia, but the exact biological mechanisms remain unclear. In this review, we attempt to understand the neurobiological pathways that link cannabis use to schizophrenia. This has been an area of great debate; despite similarities between cannabis users and schizophrenia patients, the evidence is not sufficient to establish cause-and-effect. There have been advances in the understanding of the mechanisms of cannabis dependence as well as the role of the cannabinoid system in the development of psychosis and schizophrenia. The neurobiological mechanisms associated with the development of psychosis and effects from cannabis use may be similar but remain elusive. In order to better understand these associations, this paper will show common neurobiological and neuroanatomical changes as well as common cognitive dysfunction in cannabis users and patients of schizophrenia. We conclude that epidemiologic evidence highlights potential causal links; however, neurobiological evidence for causality remains weak.

Clozapine response and pre-treatment EEG-is there some kind of relationship.

BACKGROUND: Clozapine has been used widely in the management of treatment-resistant schizophrenia. The present study aims at determining whether pre-treatment electroencephalography (EEG) abnormalities would serve as a marker for response to clozapine treatment. SUBJECTS AND METHODS: This was a cross-sectional study done in a tertiary care center in Mumbai where patients diagnosed with schizophrenia using DSM-IV criteria and resistant schizophrenia using Kane criteria were assessed using EEG prior to starting clozapine treatment. They were rated for symptomatic improvement using the Positive and Negative Syndrome Scale (PANSS) along with Clinical Global Improvement for Severity (CGI-S). The results were statistically analysed and presented. RESULTS: 55 out of the 80 patients in the study showed baseline EEG abnormalities. The mean duration of illness in the patients were 2.65 years. Slow wave and background EEG abnormalities were common in pre-treatment EEG. 36.4% patients in the study showed clinical response. Patients with negative symptoms and baseline EEG abnormalities showed better response. CONCLUSIONS: The study was circumscribed and had many limitations due to a small sample size. The relation between pre-treatment EEG abnormalities and clozapine response could not be statistically correlated and it could not be ascertained to be a marker for response to clozapine therapy.

Cannabis and psychosis: Neurobiology.

Cannabis is a known risk factor for schizophrenia, although the exact neurobiological process through which the effects on psychosis occur is not well-understood. In this review, we attempt to develop and discuss a possible pathway for the development of psychosis. We examine the neurobiological changes due to cannabis to see if these changes are similar to those seen in schizophrenic patients the findings show similarities; however, these mere similarities cannot establish a 'cause-effect' relationship as a number of people with similar changes do not develop schizophrenia. Therefore, the 'transition-to-psychosis' due to cannabis, despite being a strong risk factor, remains uncertain based upon neurobiological changes. It appears that other multiple factors might be involved in these processes which are beyond neurobiological factors. Major advances have been made in understanding the underpinning of marijuana dependence, and the role of the cannabinoid system, which is a major area for targeting medications to treat marijuana withdrawal and dependence, as well as other addictions is of now, it is clear that some of the similarities in the neurobiology of cannabis and schizophrenia may indicate a mechanism for the development of psychosis, but its trajectories are undetermined.

Perspectives on neurological patient registries: a literature review and focus group study.

BACKGROUND: Patient registries represent a well-established methodology for prospective data collection with a wide array of applications for clinical research and health care administration. An examination and synthesis of registry stakeholder perspectives has not been previously reported in the literature. METHODS: To inform the development of future neurological registries we examined stakeholder perspectives about such registries through a literature review followed by 3 focus groups comprised of a total of 15 neurological patients and 12 caregivers. RESULTS: (1) LITERATURE REVIEW: We identified 6,435 abstracts after duplicates were removed. Of these, 410 articles underwent full text review with 24 deemed relevant to perspectives about neurological and non-neurological registries and were included in the final synthesis. From a patient perspective the literature supports altruism, responsible use of data and advancement of research, among others, as motivating factors for participating in a patient registry. Barriers to participation included concerns about privacy and participant burden (i.e. extra clinic visits and associated costs). (2) Focus groups: The focus groups identified factors that would encourage participation such as: having a clear purpose; low participant burden; and being well-managed among others. CONCLUSIONS: We report the first examination and synthesis of stakeholder perspectives on registries broadly with a specific focus on neurological patient registries. The findings of the broad literature review were congruent with the neurological patient and caregiver focus groups. We report common themes across the literature and the focus groups performed. Stakeholder perspectives need to be considered when designing and operating patient registries. Emphasizing factors that promote participation and mitigating barriers may enhance patient recruitment.

Cerebral blood flow quantification in swine using pseudo-continuous arterial spin labeling.

PURPOSE: To develop quantitative cerebral blood flow (CBF) imaging using pseudo-continuous arterial spin labeling (PCASL) in swine, accounting for their cerebrovascular anatomy and physiology. MATERIALS AND METHODS: Five domestic pigs (2.5-3 months, 25 kg) were used in these studies. The orientation of the labeled arteries, T1bl , M0bl , and T1gm were measured in swine. Labeling parameters were tuned with respect to blood velocity to optimize labeling efficiency based on the data collected from three subjects. Finally, CBF and arterial transit time (ATT) maps for two subjects were created from PCASL data to determine global averages. RESULTS: The average labeling efficiency over measured velocities of 5-18 cm/s was 0.930. The average T1bl was 1546 ms, the average T1gm was 1224 ms, and the average blood-to-white matter ratio of M0 was 1.25, which was used to find M0bl . The global averages over the subjects were 54.05 mL/100 g tissue/min CBF and 1261 ms ATT. CONCLUSION: This study demonstrates the feasibility of PCASL for CBF quantification in swine. Quantification of CBF using PCASL in swine can be further developed as an accessible and cost-effective model of human cerebral perfusion for investigating injuries that affect blood flow.

The CNDR: collaborating to translate new therapies for Canadians.

BACKGROUND: Patient registries represent an important method of organizing "real world" patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry. METHODS: We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR). RESULTS: The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 "index disease" patients. Another 618 "non-index" patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. "Index disease" patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS. CONCLUSIONS: The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.

Clinical risk of stigma and discrimination of mental illnesses: Need for objective assessment and quantification.

Stigma and discrimination continue to be a reality in the lives of people suffering from mental illness, particularly schizophrenia, and prove to be one of the greatest barriers to regaining a normal lifestyle and health. Research advances have defined stigma and assessed its implications and have even examined intervention strategies for dealing with stigma. We are of the opinion that stigma is a potential clinical risk factor. It delays treatment seeking, worsens course and outcome, reduces compliance, and increases the risk of relapse; causing further disability, discrimination, and isolation even in persons who have accessed mental health services. The delay in treatment due to stigma causes potential complications like suicide, violence, harm to others, and deterioration in capacity to look after one's physical health. These are preventable clinical complications. In order to deal with the impact of stigma on an individual basis, it needs to be (i) assessed during routine clinical examination, (ii) assessed for quantification in order to obtain measurable objective deliverables, and (iii) examined if treatment can reduce stigma and its impact on individuals. New and innovative anti-stigma programs are required that are clinically driven in order to see the change in life of an individual by removing potential risks. The basic requirement for dealing with an individual's stigma perception/experience is its proper assessment for origin and impact in both a qualitative and quantitative manner. We further argue that quantification would allow for regular assessment and offer more effective intervention for patients. It will also be helpful in identifying modifiable social factors to enhance quality of care planning for management in hospitals and communities. The objective of quantification is to facilitate developing an approach to bring the assessment of stigma into clinical work and formulating customized strategies to deal with stigma at the patient level. It would be expected that the assessment of stigma would become a part of routine clinical assessment to identify barriers to outcome. This article discusses the need for quantification of patients' experiences of mental illness stigma.

Dimensions of suicidality: analyzing the domains of the SIS-MAP Suicide Risk Assessment Instrument and the development of a brief screener.

This study aimed at validating the domains of suicidality assessed by the Scale for Impact of Suicidality-Management, Assessment and Planning of Care (SIS-MAP) and creating a brief screener based on the full scale. A total of 50 individuals with suicidal ideation were given the SIS-MAP interview. Support was found for these domains of suicide risk; in particular, the subscales of ideation and protective factors for suicide risk were highly reliable. For each domain of suicidality, items most predictive of total risk index scores were selected to create a brief screener aimed at expediting the assessment process. The screener was reliable, predicted overall suicide risk index scores, and approached significance in predicting subsequent suicide attempts.