Reducing all-cause mortality among patients with psychiatric disorders: a population-based study

Background:

Among patients with psychiatric disorders, there are 10 times as many preventable deaths from physical disorders as there are from suicide. We investigated whether compulsory community treatment, such as community treatment orders, could reduce all-cause mortality among patients with psychiatric disorders.

Methods:

We conducted a population-based survival analysis of an inception cohort using record linking. The study period extended from November 1997 to December 2008. The cohort included patients from all community-based and inpatient psychiatric services in Western Australia (state population 1.8 million). We used a 2-stage design of matching and Cox regression to adjust for demographic characteristics, previous use of health services, diagnosis and length of psychiatric history. We collected data on successive cohorts for each year for which community treatment orders were used to measure changes in numbers of patients, their characteristics and outcomes. Our primary outcome was 2-year all-cause mortality. Our secondary outcomes were 1-and 3-year all-cause mortality.

Results:

The study population included 2958 patients with community treatment orders (cases) and 2958 matched controls (i.e., patients with psychiatric disorders who had not received a community treatment order). The average age for cases and controls was 36.7 years, and 63.7% (3771) of participants were men. Schizophrenia and other nonaffective psychoses were the most common diagnoses (73.4%) among participants. A total of 492 patients (8.3%) died during the study. Cox regression showed that, compared with controls, patients with community treatment orders had significantly lower all-cause mortality at 1, 2 and 3 years, with an adjusted hazard ratio of 0.62 (95% confidence interval 0.45–0.86) at 2 years. The greatest effect was on death from physical illnesses such as cancer, cardiovascular disease or diseases of the central nervous system. This association disappeared when we adjusted for increased outpatient and community contacts with psychiatric services.

Interpretation:

Community treatment orders might reduce mortality among patients with psychiatric disorders. This may be partly explained by increased contact with health services in the community. However, the effects of uncontrolled confounders cannot be excluded.Mortality among patients with psychiatric disorders is higher than in the general population.¹ Chronic physical disorders such as cardiovascular disease and cancer are the main causes of death in this population, with risks 10 times that of suicide; however, such causes receive far less attention than suicides.^1,2 Patients with schizophrenia die 15–20 years earlier than people in the general population, a difference that has increased over time.^1,3 Reasons for this difference include socioeconomic disadvantage, adverse effects of medication and reduced access to health care.^4,5There are limited data on possible interventions aimed at preventing such deaths, most of which stress regular monitoring of physical status, peer support and collaboration with primary care.^6,7 One study from Victoria, Australia, found that patients on conditional release from hospital had lower mortality than expected when use of community care, age, sex, inpatient experience and diagnosis were taken into account.⁸ However, 10% of these patients had dementia or other diseases of the nervous system, and patients with these diagnoses made up 29% of the deaths in the study. Dementia is not a typical indication for compulsory community treatment. In addition, Victoria has one of the highest levels of use of community treatment orders, about 60 per 100 000 population; thus, those results may not be generalizable to other locales.⁸ Although the authors controlled for time at risk, death could occur from 1 day to 11 years after the index date;⁹ most evaluations of community treatment orders are limited to 1 or 2 years after the order is issued.^9,10 Finally, the results were not adjusted for patients’ marital status, education, country of birth, indigenous status or use of health services before the introduction of community treatment orders. Adjusting for these variables could reduce the bias inherent in drawing cases and controls from the same jurisdiction given the difficulties in controlling for all possible reasons for issuing these orders once they have been introduced.We sought to assess the impact of community treatment orders on 1-, 2-, and 3-year survival in Western Australia. Community treatment orders provide a legal framework within which patients with a serious mental disorder are required to accept psychiatric treatment while living outside hospital. These orders are used across both Canada and Australia, are of similar duration in both countries, and are clinician-initiated rather than court-ordered (in contrast to the United States).^10,11 Unlike in Canada, patients in Australia can be given community treatment orders without having been previously admitted to hospital. In practice, patients in both countries spend similar amounts of time in hospital before being given a community treatment order.¹²We focused on deaths from physical illness, rather than suicides, as these are the most common causes of preventable death among people with severe mental illness.^1,2 We thought that patients with community treatment orders would have lower mortality because of improved engagement with health services, thus allowing greater monitoring and management of physical health. Greater engagement would be shown via increased outpatient contacts following the receipt of a community treatment order, which would influence any association between compulsory community treatment and mortality.     

Long-term mortality in patients with tuberculous meningitis: a Danish nationwide cohort study

Background

With high short-term mortality and substantial excess morbidity among survivors, tuberculous meningitis (TBM) is the most severe manifestation of extra-pulmonary tuberculosis (TB). The objective of this study was to assess the long-term mortality and causes of death in a TBM patient population compared to the background population.

Methods

A nationwide cohort study was conducted enrolling patients notified with TBM in Denmark from 1972–2008 and alive one year after TBM diagnosis. Data was extracted from national registries. From the background population we identified a control cohort of individuals matched on gender and date of birth. Kaplan-Meier survival curves and Cox regression analysis were used to estimate mortality rate ratios (MRR) and analyse causes of death.

Findings

A total of 55 TBM patients and 550 individuals from the background population were included in the study. Eighteen patients (32.7%) and 107 population controls (19.5%) died during the observation period. The overall MRR was 1.79 (95%CI: 1.09–2.95) for TBM patients compared to the population control cohort. TBM patients in the age group 31–60 years at time of diagnosis had the highest relative risk of death (MRR 2.68; 95%CI 1.34–5.34). The TBM patients had a higher risk of death due to infectious disease, but not from other causes of death.

Conclusion

Adult TBM patients have an almost two-fold increased long-term mortality and the excess mortality stems from infectious disease related causes of death.     

Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized by tumors on the vestibular branch of the VIII cranial nerve, but other types of nervous system tumors usually occur as well. Genotype-phenotype correlations are well documented for overall NF2 disease severity but have not been definitively evaluated for specific types of non-VIII nerve tumors. We evaluated genotype-phenotype correlations for various types of non-VIII nerve tumors in 406 patients from the population-based United Kingdom NF2 registry, using regression models with the additional covariates of current age and type of treatment center (specialty or nonspecialty). The models also permitted consideration of intrafamilial correlation. We found statistically significant genotype-phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. The type of constitutional NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors.     

Living alone and alcohol-related mortality: a population-based cohort study from Finland

Background

Social isolation and living alone are increasingly common in industrialised countries. However, few studies have investigated the potential public health implications of this trend. We estimated the relative risk of death from alcohol-related causes among individuals living alone and determined whether this risk changed after a large reduction in alcohol prices.

Methods and Findings

We conducted a population-based natural experimental study of a change in the price of alcohol that occurred because of new laws enacted in Finland in January and March of 2004, utilising national registers. The data are based on an 11% sample of the Finnish population aged 15–79 y supplemented with an oversample of deaths. The oversample covered 80% of all deaths during the periods January 1, 2000–December 31, 2003 (the four years immediately before the price reduction of alcohol), and January 1, 2004–December 31, 2007 (the four years immediately after the price reduction). Alcohol-related mortality was defined using both underlying and contributory causes of death. During the 8-y follow-up about 18,200 persons died due to alcohol-related causes. Among married or cohabiting people the increase in alcohol-related mortality was small or non-existing between the periods 2000–2003 and 2004–2007, whereas for those living alone, this increase was substantial, especially in men and women aged 50–69 y. For liver disease in men, the most common fatal alcohol-related disease, the age-adjusted risk ratio associated with living alone was 3.7 (95% confidence interval 3.3, 4.1) before and 4.9 (95% CI 4.4, 5.4) after the price reduction (p<0.001 for difference in risk ratios). In women, the corresponding risk ratios were 1.7 (95% CI 1.4, 2.1) and 2.4 (95% CI 2.0, 2.9), respectively (p ≤ 0.01). Living alone was also associated with other mortality from alcohol-related diseases (range of risk ratios 2.3 to 8.0) as well as deaths from accidents and violence with alcohol as a contributing cause (risk ratios between 2.1 and 4.7), both before and after the price reduction.

Conclusions

Living alone is associated with a substantially increased risk of alcohol-related mortality, irrespective of gender, socioeconomic status, or the specific cause of death. The greater availability of alcohol in Finland after legislation-instituted price reductions in the first three months of 2004 increased in particular the relative excess in fatal liver disease among individuals living alone. Please see later in the article for the Editors'' Summary     

Mortality among patients with hypertension from 1995 to 2005: a population-based study

Background

We have reported that the prevalence of diagnosed hypertension increased by 60% from 1995 to 2005 in Ontario. In the present study, we asked whether this increase is explained by a decrease in the mortality rate.

Methods

We performed a population-based cohort study using linked administrative data for Ontario, a Canadian province with over 12 million residents. We identified prevalent cases of hypertension using a validated case-definition algorithm for hypertension, and we examined trends in mortality from 1995 to 2005 among adults aged 20 years and older with hypertension.

Results

The age-and sex-adjusted mortality among patients with hypertension decreased from 11.3 per 1000 people in 1995 to 9.6 per 1000 in 2005 (p < 0.001), which is a relative reduction of 15.5%. We found that the relative decrease in age-adjusted mortality was higher among men than among women (–22.2% v. –7.3%, p < 0.001).

Interpretation

Mortality rates among patients with hypertension have decreased. Along with an increasing incidence, decreased mortality rates may contribute to the increased prevalence of diagnosed hypertension. Sex-related discrepancies in the reduction of mortality warrant further investigation.High blood pressure is the leading risk factor for mortality around the world.^1,2 Over a decade ago, the Canadian Heart Health Survey reported that 42% of Canadian adults with hypertension were unaware that they had the condition and that only 16% of cases were treated and controlled.³ More recent studies in the United States⁴ and England⁵ have reported improved awareness, treatment and control among adults with hypertension. In addition, increased initiation of hypertensive medications among elderly patients⁶ and increased use of polytherapy for treating hypertension have been reported.⁷ Given that blood pressure control has been shown to reduce mortality, one might expect that enhanced awareness and treatment of hypertension has led to improvements in mortality among patients with this condition. Greater survival of patients with hypertension would contribute to an overall increase in the prevalence of hypertension.In another article in this issue of CMAJ, we report that the prevalence of diagnosed hypertension among adults increased by 60% from 1995 to 2005, which greatly surpassed prior projections for the developed world.⁸ Previous projections may have underestimated prevalence⁹ because researchers did not adequately account for the contribution of increased survival. Indeed, the increased prevalence cannot be explained by increased incidence alone, because the incidence of hypertension increased by 25.7% between 1997 and 2004 whereas prevalence increased by 35.5% during that same period. In the present study, our objective was to examine the mortality rates among patients with hypertension to determine whether declining mortality also contributed to the rising prevalence of hypertension.     

Bacteriology of abscesses of the central nervous system: a multicentre prospective study.

Pus from 46 patients with abscesses of the central nervous system (CNS) was examined for bacteria; bacteria were found in all patients. Streptococci were isolated from 36 patients and most isolates were Streptococcus milleri, Lancefield Group F, Ottens and Winkler type O III. Staphylococci were isolated from nine patients, organisms of the bacteroides group from 11, Proteus spp from seven, Klebsiella aerogenes from one, and Haemophilus aphrophilus from one. Pure cultures predominated over mixed cultures. Streptococci were isolated from abscesses of all types, and at all sites, but members of the Enterobacteriaceae and of the bacteroides group were isolated, in mixed cultures, principally from abscesses of the temporal lobe secondary to infection of the middle ear. Staphylococci predominated in abscesses that followed accidental or surgical trauma. Compared with fully sensitive control organisms, microbes infecting half the patients were resistant to penicillin. The prognosis of abscess of the CNS is grave, and the microbiological findings have important consequences for treatment. Prompt inoculation of specimens to culture plates and prompt incubation are mandatory if bacteria are to be cultured. Inhibitors of antimicrobial agents should be added to culture media if antibiotics have been administered. Provided that the site of the abscess and the antecedent history are ascertainable, the neurosurgeon should be able to start appropriate treatment while awaiting the results of culture.     

New approaches in the study of the neuroplasticity process in patients with central nervous system lesions

Methods that, on the one hand, can ensure patient’s mobility and, on the other hand, activate afferent inputs are the main in the rehabilitation treatment. Recent studies have shown that plasticity is the structural basis of recovery after central nervous system lesions. Reorganization of cortical areas, increase in the efficiency of the functioning of preserved structures; and active use of alternative ascending pathways, e.g., intensification of afferent input, constitute the anatomical basis of plasticity. However, sensory correction methods, without accounting of functional condition of patients, may lead to the formation of pathological symptoms: spasticity, hyperreflexia, etc. So, the main aim is to study adequate management of the neuroplasticity process. This problem cannot be solved without modern methods of neuroimaging and brain mapping. The new approach for the study of cortical mechanisms of neuroplasticity, responsible for locomotion, was developed in the present study. This approach is an integrated use of functional magnetic resonance imaging (fMRI) and navigation transcranial magnetic stimulation (nTMS). It has been shown that vast fMRI activation area in the first and second sensorimotor areas emerges with a passive sensorimotor paradigm usage that imitates backing load during walking. The Korvit mechanical stimulator of backing zones of footsteps is used to create this paradigm. The nTMS examination used after fMRI helps to localize motor representation of muscles which control locomotion more accurately. We assume that the new approach can be used for studying the neuroplasticity process and assessing neuroplasticity changes when taking rehabilitation measures to restore and correct the walking process.     

Congenital central nervous system malformations and vinyl chloride monomer exposure: a community study

Incidence rates for central nervous system (CNS) malformations in infants born to residents of Kanawha County, West Virginia, 1970-1974, were significantly higher than comparable United States rates during those years. Since Kanawha County contains a polyvinyl chloride (PVC) polymerization plant, a case-control study was conducted on the possible relationship between the occurrence of CNS defects and parental occupational or residential exposure to vinyl chloride monomer emissions from this plant. No relationship with parental occupation was found. While a tendency was noted for residences of case families to be located in an area northeast of the plant, this observation did not entirely correlate with existing data on local patterns of wind direction and air pollution.     

Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study

Cross-sectional studies have repeatedly suggested peripheral blood monocyte telomere length as a biomarker of aging. To test this suggestion in a large population-based follow-up study of the oldest old, we measured telomere length at baseline in 598 participants of the Leiden 85-plus Study (mean age at baseline 89.8 years). We also obtained second telomere measurements from 81 participants after an average time span of between 3.9 and 12.9 years. Telomere length at baseline was not predictive for mortality (P > 0.40 for all-cause, cardiovascular causes, cancer or infectious diseases, Cox regression for gender-adjusted tertiles of telomere length) or for the incidence of dementia (P = 0.78). Longitudinally, telomere length was highly unstable in a large fraction of participants. We conclude that blood monocyte telomere length is not a predictive indicator for age-related morbidity and mortality at ages over 85 years, possibly because of a high degree of telomere length instability in this group.     

New era of optogenetics: from the central to peripheral nervous system

Abstract

Optogenetics has recently gained recognition as a biological technique to control the activity of cells using light stimulation. Many studies have applied optogenetics to cell lines in the central nervous system because it has the potential to elucidate neural circuits, treat neurological diseases and promote nerve regeneration. There have been fewer studies on the application of optogenetics in the peripheral nervous system. This review introduces the basic principles and approaches of optogenetics and summarizes the physiology and mechanism of opsins and how the technology enables bidirectional control of unique cell lines with superior spatial and temporal accuracy. Further, this review explores and discusses the therapeutic potential for the development of optogenetics and its capacity to revolutionize treatment for refractory epilepsy, depression, pain, and other nervous system disorders, with a focus on neural regeneration, especially in the peripheral nervous system. Additionally, this review synthesizes the latest preclinical research on optogenetic stimulation, including studies on non-human primates, summarizes the challenges, and highlights future perspectives. The potential of optogenetic stimulation to optimize therapy for peripheral nerve injuries (PNIs) is also highlighted. Optogenetic technology has already generated exciting, preliminary evidence, supporting its role in applications to several neurological diseases, including PNIs.     

Repair of the central nervous system: Lessons from lesions in leeches

In contrast to the limited repair observed in the mammalian central nervous system (CNS), injured neurons in the leech reliably regenerate synapses and restore function with remarkable accuracy at the level of individual neurons. New and recent results reveal important roles for microglial cells and extracellular matrix components, including laminin, in repair. Tissue culture experiments have permitted isolation of neurons and manipulation of their environment, providing insights into the influence of substrate, electrical activity, and other cells, including microglia, on axon growth and synapse formation. The results account for distinctive features of successful repair in the adult leech, where axonal sprouting and target selection can be influenced by unequal competition between neurons. Differences between the formation of connections during embryonic development and repair in the adult include dissimilarities in the roles of glia and microglia in adults and embryos, suggesting that axon growth during regeneration in the CNS is not simply a recapitulation of processes observed during embryonic development. It may be possible in the future to improve mammalian CNS regeneration by recruiting cells whose counterparts in the leech have been identified as instrumental in repair. © 1995 John Wiley & Sons, Inc.     

Extracellular matrix of the central nervous system: from neglect to challenge

The basic concept, that specialized extracellular matrices rich in hyaluronan, chondroitin sulfate proteoglycans (aggrecan, versican, neurocan, brevican, phosphacan), link proteins and tenascins (Tn-R, Tn-C) can regulate cellular migration and axonal growth and thus, actively participate in the development and maturation of the nervous system, has in recent years gained rapidly expanding experimental support. The swift assembly and remodeling of these matrices have been associated with axonal guidance functions in the periphery and with the structural stabilization of myelinated fiber tracts and synaptic contacts in the maturating central nervous system. Particular interest has been focused on the putative role of chondroitin sulfate proteoglycans in suppressing central nervous system regeneration after lesions. The axon growth inhibitory properties of several of these chondroitin sulfate proteoglycans in vitro, and the partial recovery of structural plasticity in lesioned animals treated with chondroitin sulfate degrading enzymes in vivo have significantly contributed to the increased awareness of this long time neglected structure.     

The radioresponse of the central nervous system: a dynamic process

Radiation continues to be a major treatment modality for tumors located within and close to the central nervous system (CNS). Consequently, alleviating or protecting against radiation-induced CNS injury would be of benefit in cancer treatment. However, the rational development of such interventional strategies will depend on a more complete understand-ing of the mechanisms responsible for the development of this form of normal tissue injury. Whereas the vasculature and the oligodendrocyte lineage have traditionally been considered the primary radiation targets in the CNS, in this review we suggest that other phenotypes as well as critical cellular interactions may also be involved in determining the radio-response of the CNS. Furthermore, based on the assumption that the CNS has a limited repertoire of responses to injury, the reaction of the CNS to other types of insults is used as a framework for modeling the pathogenesis of radiation-induced damage. Evidence is then provided suggesting that, in addition to acute cell death, radiation induces an intrinsic recovery/repair response in the form of specific cytokines and may     

Isolation of mononuclear cells from the central nervous system of rats with EAE

Whether studying an autoimmune disease directed to the central nervous system (CNS), such as experimental autoimmune encephalomyelitis (EAE, 1), or the immune response to an infection of the CNS, such as poliomyelitis, Lyme neuroborreliosis, or neurosyphilis, it is often necessary to isolate the CNS-infiltrating immune cells.In this video-protocol we demonstrate how to isolate mononuclear cells (MNCs) from the CNS of a rat with EAE. The first step of this procedure requires a cardiac perfusion of the rodent with a saline solution to ensure that no blood remains in the blood vessels irrigating the CNS. Any blood contamination will artificially increase the number of apparent CNS-infiltrating MNCs and may alter the apparent composition of the immune infiltrate. We then demonstrate how to remove the brain and spinal cord of the rat for subsequent dilaceration to prepare a single-cell suspension. This suspension is separated on a two-layer Percoll gradient to isolate the MNCs. After washing, these cells are then ready to undergo any required procedure. Mononuclear cells isolated using this procedure are viable and can be used for electrophysiology, flow cytometry (FACS), or biochemistry. If the technique is performed under sterile conditions (using sterile instruments in a tissue culture hood) the cells can also be grown in tissue culture medium. A given cell population can be further purified using either magnetic separation procedures or a FACS.     

Membranes with dopamine receptors coupled to G proteins: Purification from theLymnaea central nervous system

A membrane fraction, which contained dopamine receptors and heterotrimeric G proteins, was purified from homogenate of molluscan (Lymnaea) CNS tissues. Radioligand binding analysis with the use of [7.8-³H] dopamine detected the presence of a high-affinity binding site in this fraction. [7.8-³H] Dopamine was displaced in a dose-dependent manner by dopamine antagonists, S(-)-sulpiride, (±)-SKF83566, and fluphenazine. Radioligand binding analysis of purified membranes with the use of labelled GDP showed the presence of a high affinity binding site withB _max=92±5 pmol/mg of protein andK _d =64±10 nM. GDP, in contrast to GTP, markedly increased [7.8-³H] dopamine binding in the absence of metal cations (the maximum increase was 2.5-fold). Added separately, Na and Mg ions decreased the stimulatory influence of GDP. Jointly, these ions completely abolished this GDP influence on the [7.8-³H] dopamine binding. In the membrane fraction, GTPase activity in the presence of dopamine increased during an initial period and then decreased below the basal level. Therefore, we have demonstrated that in our experiments dopamine receptors in the purified membrane fraction are functionally coupled with heterotrimeric G proteins, but their interaction displays some specific features.