Absolute risks of self-harm and interpersonal violence by diagnostic category following first discharge from inpatient psychiatric care.

BACKGROUND: Persons discharged from inpatient psychiatric services are at greatly elevated risk of harming themselves or inflicting violence on others, but no studies have reported gender-specific absolute risks for these two outcomes across the spectrum of psychiatric diagnoses. We aimed to estimate absolute risks for self-harm and interpersonal violence post-discharge according to gender and diagnostic category. METHODS: Danish national registry data were utilized to investigate 62,922 discharged inpatients, born 1967-2000. An age and gender matched cohort study was conducted to examine risks for self-harm and interpersonal violence at 1 year and at 10 years post-discharge. Absolute risks were estimated as cumulative incidence percentage values. RESULTS: Patients diagnosed with substance misuse disorders were at especially elevated risk, with the absolute risks for either self-harm or interpersonal violence being 15.6% (95% CI 14.9, 16.3%) of males and 16.8% (15.6, 18.1%) of females at 1 year post-discharge, rising to 45.7% (44.5, 46.8%) and 39.0% (37.1, 40.8%), respectively, within 10 years. Diagnoses of personality disorders and early onset behavioral and emotional disorders were also associated with particularly high absolute risks, whilst risks linked with schizophrenia and related disorders, mood disorders, and anxiety/somatoform disorders, were considerably lower. CONCLUSIONS: Patients diagnosed with substance misuse disorders, personality disorders and early onset behavioral and emotional disorders are at especially high risk for internally and externally directed violence. It is crucial, however, that these already marginalized individuals are not further stigmatized. Enhanced care at discharge and during the challenging transition back to life in the community is needed.

Suicide and death by other causes among patients with a severe mental illness: cohort study comparing risks among patients discharged from inpatient care v. those treated in the community.

AIMS: People diagnosed with a severe mental illness (SMI) are at elevated risk of dying prematurely compared to the general population. We aimed to understand the additional risk among people with SMI after discharge from inpatient psychiatric care, when many patients experience an acute phase of their illness. METHODS: In the Clinical Practice Research Datalink (CPRD) GOLD and Aurum datasets, adults aged 18 years and older who were discharged from psychiatric inpatient care in England between 2001 and 2018 with primary diagnoses of SMI (schizophrenia, bipolar disorder, other psychoses) were matched by age and gender with up to five individuals with SMI and without recent hospital stays. Using survival analysis approaches, cumulative incidence and adjusted hazard ratios were estimated for all-cause mortality, external and natural causes of death, and suicide. All analyses were stratified by younger, middle and older ages and also by gender. RESULTS: In the year after their discharge, the risk of dying by all causes examined was higher than among individuals with SMI who had not received inpatient psychiatric care recently. Suicide risk was 11.6 times (95% CI 6.4-20.9) higher in the first 3 months and remained greater at 2-5 years after discharge (HR 2.3, 1.7-3.2). This risk elevation remained after adjustment for self-harm in the 6 months prior to the discharge date. The relative risk of dying by natural causes was raised in the first 3 months (HR 1.6, 1.3-1.9), with no evidence of elevation during the second year following discharge. CONCLUSIONS: There is an additional risk of death by suicide and natural causes for people with SMI who have been recently discharged from inpatient care over and above the general risk among people with the same diagnosis who have not recently been treated as an inpatient. This mortality gap shows the importance of continued focus, following discharge, on individuals who require inpatient care.

Self-harm and violent criminality linked with parental death during childhood.

BACKGROUND: Adverse health and social outcomes are known to occur more frequently following parental death during childhood, but evidence is lacking for comparing long-term risks of internalised v. externalised harm. METHODS: This national register-based cohort study consisted of Danish persons born 1970-2000. The Civil Registration System and National Causes of Death Register were linked to ascertain parental deaths by cause before cohort members' 15th birthdays. From age 15 years, hospital-treated self-harm episodes were ascertained through linkage to the National Patient Register and the Psychiatric Central Research Register, and violent crimes were identified via linkage to the National Crime Register. Hazard ratio and cumulative incidence values were estimated. RESULTS: Self-harm and violent criminality risks were elevated following parental death during childhood. Covariate adjustment for gender, birth year and first-degree relatives' mental illnesses attenuated these associations, although significantly heightened risks persisted. The estimated hazard ratios did not differ greatly according to which parent died, but losing both parents conferred particularly large risk increases. Risks for both adverse outcomes were higher in relation to unnatural v. natural parental death; violent criminality risk was especially raised among individuals exposed to parental death by unnatural causes other than suicide. The association was strongest when pre-school age children experienced parental death. CONCLUSIONS: Effective early intervention is needed to help youngsters who have experienced the death of one or both parents to develop immediate and sustained coping strategies. Enhanced cooperation between health and social services and criminal justice agencies may mitigate risks for these two destructive behaviours.

Psychiatric morbidity and suicidal behaviour in psoriasis: a primary care cohort study.

BACKGROUND: Psychological distress among people with psoriasis may lead to elevated risks of suicide and nonfatal self-harm. OBJECTIVES: To investigate psychiatric comorbidity, psychotropic medication prescribing and risk of suicidality in people with psoriasis. METHODS: A cohort of patients with psoriasis (1998-2014) was delineated using the Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics and Office for National Statistics mortality records. Each patient with psoriasis was matched with up to 20 patients without psoriasis on age, sex and general practice. A stratified Cox regression model was used to estimate the hazard ratios (HRs) for suicide or nonfatal self-harm risks adjusted for socioeconomic status. RESULTS: At baseline, among 56 961 and 876 919 patients with and without psoriasis, higher prevalence for histories of alcohol misuse, bipolar disorder, depression, anxiety disorders, self-harm and psychotropic drug prescription were observed. The deprivation-adjusted HR indicated lower suicide risk in people with psoriasis [HR 0·59, 95% confidence interval (CI) 0·41-0·85]. The risk of suicide varied according to age: it was lower in people with psoriasis diagnosed at ≥ 40 years (HR 0·38, 95% CI 0·21-0·66), whereas there was no difference in risk of suicide in people with psoriasis diagnosed before age 40 years (HR 0·92, 95% CI 0·58-1·46). Conversely, there was a small increased risk for self-harm (HR 1·15, 95% CI 1·04-1·27) associated with psoriasis. CONCLUSIONS: The prevalence of mental illness was raised in people with psoriasis, and this may lead to a greater risk of self-harm. Nevertheless, having psoriasis does not appear to be associated with an increased risk of suicide. Healthcare professionals caring for patients with psoriasis should continue to monitor and tackle effectively the psychological needs of these individuals.

Suicide risk linked with clinical consultation frequency, psychiatric diagnoses and psychotropic medication prescribing in a national study of primary-care patients.

BACKGROUND: Little is known about the precursors of suicide risk among primary-care patients. This study aimed to examine suicide risk in relation to patterns of clinical consultation, psychotropic drug prescribing, and psychiatric diagnoses. METHOD: Nested case-control study in the Clinical Practice Research Datalink (CPRD), England. Patients aged ⩾16 years who died by suicide during 2002-2011 (N = 2384) were matched on gender, age and practice with up to 20 living control patients (N = 46 899). RESULTS: Risk was raised among non-consulting patients, and increased sharply with rising number of consultations in the preceding year [⩾12 consultations v. 1: unadjusted odds ratio (OR) 6.0, 95% confidence interval (CI) 4.9-7.3]. Markedly elevated risk was also associated with the prescribing of multiple psychotropic medication types (⩾5 types v. 0: OR 62.6, CI 44.3-88.4) and with having several psychiatric diagnoses (⩾4 diagnoses v. 0: OR 31.1, CI 19.3-50.1). Risk was also raised among patients living in more socially deprived localities. The confounding effect of multiple psychotropic drug types largely accounted for the rising risk gradient observed with increasing consultation frequency. CONCLUSIONS: A greater proportion of patients with several psychiatric diagnoses, those prescribed multiple psychotropic medication types, and those who consult at very high frequency might be considered for referral to mental health services by their general practitioners. Non-consulters are also at increased risk, which suggests that conventional models of primary care may not be effective in meeting the needs of all people in the community experiencing major psychosocial difficulties.

Use of a geographic information system to map cases of measles in real-time during an outbreak in Dublin, Ireland, 2011.

In 2011, there was a large measles outbreak in Dublin. Nationally 285 cases were notified to the end of December 2011, and 250 (88%) were located in the Dublin region. After the first case was notified in week 6, numbers gradually increased, with 25 notified in June and a peak of 53 cases in August. Following public health intervention including a measles-mumps-rubella (MMR) vaccination campaign, no cases were reported in the Dublin region in December 2011. Most cases (82%) were children aged between 6 months and 14 years, and 46 cases (18%) were under 12 months-old. This is the first outbreak in Dublin to utilise a geographic information system for plotting measles cases on a digital map in real time. This approach, in combination with the analysis of case notifications, assisted the department of public health in demonstrating the extent of the outbreak. The digital mapping documented the evolution of two distinct clusters of 87 (35%) cases. These measles cases were infected with genotype D4-Manchester recently associated with large outbreaks across Europe. The two clusters occurred in socio-economically disadvantaged areas and were attributable to inadequate measles vaccination coverage due in part to the interruption of a school-based MMR2 vaccination programme.

First reported cases of human adenovirus serotype 14p1 infection, Ireland, October 2009 to July 2010.

We report the first nine confirmed cases of human adenovirus 14p1 infection (HAdV-14p1), identified at different locations in Ireland between October 2009 and July 2010. These were the first notifications in Ireland and all were sporadic cases. Following these notifications, the Health Protection Surveillance Centre set up an enhanced surveillance system for HAdV-14p1 infection. Seven cases were male and five were aged less than one year. Three patients died, giving a case fatality rate of 33%. It should be noted that cases presented here were diagnosed on presentation to hospital and may represent the severe end of the spectrum of HAdV 14 disease in Ireland.

Transgene expression and effective gene silencing in vagal afferent neurons in vivo using recombinant adeno-associated virus vectors.

Vagal afferent fibres innervating thoracic structures such as the respiratory tract and oesophagus are diverse, comprising several subtypes of functionally distinct C-fibres and A-fibres. Both morphological and functional studies of these nerve subtypes would be advanced by selective, effective and long-term transduction of vagal afferent neurons with viral vectors. Here we addressed the hypothesis that vagal sensory neurons can be transduced with adeno-associated virus (AAV) vectors in vivo, in a manner that would be useful for morphological assessment of nerve terminals, using enhanced green fluorescent protein (eGFP), as well as for the selective knock-down of specific genes of interest in a tissue-selective manner. We found that a direct microinjection of AAV vectors into the vagal nodose ganglia in vivo leads to selective, effective and long-lasting transduction of the vast majority of primary sensory vagal neurons without transduction of parasympathetic efferent neurons. The transduction of vagal neurons by pseudoserotype AAV2/8 vectors in vivo is sufficiently efficient such that it can be used to functionally silence TRPV1 gene expression using short hairpin RNA (shRNA). The eGFP encoded by AAV vectors is robustly transported to both the central and peripheral terminals of transduced vagal afferent neurons allowing for bright imaging of the nerve endings in living tissues and suitable for structure-function studies of vagal afferent nerve endings. Finally, the AAV2/8 vectors are efficiently taken up by the vagal nerve terminals in the visceral tissue and retrogradely transported to the cell body, allowing for tissue-specific transduction.

Peripheral mechanisms I: plasticity of peripheral pathways.

Cough plays a vital role in protecting the lower airways from inhaled irritants, pollutants, and infectious agents. The cough reflex exhibits remarkable plasticity, such that in the context of infectious or inflammatory respiratory diseases such as asthma, chronic bronchitis, and idiopathic pulmonary fibrosis the cough reflex can become dysregulated, leading to a chronic cough. A chronic, nonproductive (dry) cough can rob sufferers of quality of life. Plasticity of the cough reflex likely involves multiple intersecting pathways within the airways, the peripheral nerves that supply them, and the central nervous system. While further studies are needed to determine the presence and relevance of many of these specific pathways in cough associated with chronic respiratory disease, the last decade has yielded unprecedented insight into the molecular identity of the ion channels and associated proteins that initiate and conduct action potentials in the primary sensory nerves involved in reflexes such as cough. We now know, for instance, that members of the transient receptor potential superfamily of nonselective cation channels function as transducers that convert specific external stimuli into neuronal activation. We also know that certain Na+ and K+ channels play specialized roles in regulating action potential discharge in irritant-sensing afferent nerves. In this chapter, we summarize the available information regarding factors that may modulate afferent neuron function acutely, via posttranslational modifications and over the longer term through neurotrophin-dependent alterations of the transcriptional programs of adult sensory neurons.

Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal.

Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.

Human metapneumovirus-associated respiratory tract infections in the Republic of Ireland during the influenza season of 2003-2004.

Human metapneumovirus (hMPV) is a newly identified paramyxovirus that has been associated with respiratory tract illness in children aged < 5 years, the elderly, and immunocompromised patients. This study determined the frequency of respiratory tract infections (RTIs) associated with hMPV in the Republic of Ireland. Bronchoalveolar lavage (BAL) samples from 168 adult patients and respiratory specimens from 122 children aged < 5 years were collected between September 2003 and May 2004. The virus was detected by reverse-transcription (RT)-PCR using hMPV polymerase (L) and matrix (M)-specific primers in four (2.4%) of 171 BAL specimens obtained from 168 adults. No other respiratory virus was detected in these specimens, and no hMPV RNA was detected in respiratory specimens from children during the same time period. In all four adult cases, two of whom had underlying disease, hMPV was associated with mild, self-limiting upper RTIs. The most common clinical findings included fever (3/4 patients), cough (4/4) and rhinorrhoea (3/4). No patient died as a result of these RTI episodes. Phylogenetic analysis was performed using the amplified regions of the M and fusion (F) genes of hMPV. The Irish isolates belonged to cluster 1B, and did not show a separate Irish sub-lineage.

Pharmacology of airway afferent nerve activity.

Afferent nerves in the airways serve to regulate breathing pattern, cough, and airway autonomic neural tone. Pharmacologic agents that influence afferent nerve activity can be subclassified into compounds that modulate activity by indirect means (e.g. bronchial smooth muscle spasmogens) and those that act directly on the nerves. Directly acting agents affect afferent nerve activity by interacting with various ion channels and receptors within the membrane of the afferent terminals. Whether by direct or indirect means, most compounds that enter the airspace will modify afferent nerve activity, and through this action alter airway physiology.

Inflammation-induced plasticity of the afferent innervation of the airways.

The activation of primary afferent neurons that innervate the airways leads to homeostatic and defensive reflexes. The anatomic and physiologic characteristics of these afferent fibers do not appear to be static properties but rather appear to change rapidly in response to inflammation. The threshold for activation of airway afferent neurons to various stimuli, for example, is not fixed; these fibers can be become sensitized during inflammation. A subset of nociceptive-like (C-fibers) airway afferent neurons not only participates in centrally mediated reflexes but is also thought to release neuropeptides at their peripheral terminals, leading to neurogenic inflammation. An increase in the content of tachykinins is commonly seen in inflamed tissues, and there is accumulating evidence that irritation and inflammation of the airways is associated with the induction of tachykinin synthesis in non-nociceptive airway afferent fibers that under normal conditions do not contain neuropeptides. The release of neurokinins from the peripheral terminals in the airways and their central terminals in the brain stem may contribute to the symptoms of inflammatory airway diseases. Elevated release of neurokinins from peripheral terminals may promote local inflammatory responses, and the release of neurokinins in the brainstem, together with inflammation-induced increases in the excitability of afferent fibers, may culminate in altered visceral autonomic reflex activity, changes in breathing pattern, and cough.

Inhibition of mechanical activation of guinea-pig airway afferent neurons by amiloride analogues.

1. The aim of this study was to investigate a role for Epithelial Sodium Channels (ENaCs) in the mechanical activation of low-threshold vagal afferent nerve terminals in the guinea-pig trachea/bronchus. 2. Using extracellular single-unit recording techniques, we found that the ENaC blocker amiloride, and its analogues dimethylamiloride and benzamil caused a reduction in the mechanical activation of guinea-pig airway afferent fibres. 3. Amiloride and it analogues also reduced the sensitivity of afferent fibres to electrical stimulation such that greater stimulation voltages were required to induce action potentials from their peripheral terminals within the trachea/bronchus. 4. The relative potencies of these compounds for inhibiting electrical excitability of afferent nerves were similar to that observed for inhibition of mechanical stimulation (dimethylamiloride approximately benzamil > amiloride). This rank order of potency is incompatible with the known rank order of potency for blockade of ENaCs (benzamil > amiloride >> dimethylamiloride). 5. As voltage-gated sodium channels play an important role in determining the electrical excitability of neurons, we used whole-cell patch recordings of nodose neuron cell bodies to investigate the possibility that amiloride analogues caused blockade of these channels. At the concentration required to inhibit mechanical activation of vagal nodose afferent fibres (100 microM), benzamil caused significant inhibition of voltage-gated sodium currents in neuronal cell bodies acutely isolated from guinea-pig nodose ganglia. 6. Combined, our findings suggest that amiloride and its analogues did not selectively block mechanotransduction in airway afferent neurons, but rather they reduced neuronal excitability, possibly by inhibiting voltage-gated sodium currents.

Ion channels in airway afferent neurons.

Action potentials initiated at the peripheral terminal of an afferent nerve are conducted to the central nervous system therein causing release of neurotransmitters that excite secondary neurons in the brain stem or spinal cord. Various chemicals, extremes in osmolarity and pH as well as mechanical stimuli are sensed by primary afferent nerves that innervate the airways. The processes leading to excitation of afferent nerve endings, conduction of action potentials along axons, transmitter secretion, and neuronal excitability are regulated by ions flowing through channels in the nerve membrane. Voltage-gated ion channels selective for K+ and Na+ ions allow the generation and conduction of action potentials and along with families of ion channels selective for other ions such as Ca2+ or Cl- are thought to play distinctive roles in regulating neuronal excitability and transmitter secretion. Here we discuss, in general terms, the roles played by various classes of ion channels in the activation, neurotransmitter secretion and excitability of primary afferent neurons.

Neurotrophins and asthma.

The neurotrophins are a family of peptides that promote survival, growth, and differentiation of neurons. Neurotrophins may also influence the function of nonneuronal cell types, including immune cells. The development and maintenance of asthma is thought to involve the nervous system and the immune system, but the role that neurotrophins play in asthma is unknown. The cellular sources of the neurotrophins include mast cells, lymphocytes, macrophages, epithelial cells, smooth muscle cells, and eosinophils. The activation of neurotrophin receptors in immune cells and neurons involves ligand-induced homodimerization, which leads to activation of intrinsic Trk receptor kinase. The exact consequences of activating these receptors on immune cells is unknown, but rather than having unique actions on immune cells, the neurotrophins appear to act in concert with known immune regulating factors to modulate the maturation, accumulation, proliferation, and activation of immune cells. Neurotrophins can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. These neuropeptides may be released from the central terminals of airway afferent neurons, which leads to heightened autonomic reflex activity, and increased reactivity in the airways.

Trypsin-induced, neurokinin-mediated contraction of guinea pig bronchus.

Proteases may act as cell signaling molecules via protease-activated receptors (PARs). PAR1, PAR3, and PAR4, but not PAR2, are activated by thrombin, whereas trypsin can activate PAR2 and PAR4. In this study, trypsin (3-100 nM) evoked concentration-dependent contractions of guinea pig isolated bronchus, however, thrombin (3-300 nM) was a weak spasmogen. Neither the PAR2-activating peptide SLIGRL (100 microM) nor mast cell tryptase (100 nM), a trypsin-like protease known to activate PAR2, evoked contraction. A role for neurokinins in trypsin-induced contraction is suggested by our observation that contractions to trypsin were markedly attenuated in the presence of neurokinin receptor antagonists. Depletion of neurokinins in sensory nerves with capsaicin also markedly reduced the ability of trypsin to evoke contraction. In electrophysiological studies, trypsin did not evoke action potentials in C-fiber afferents whose receptive fields were located in the trachea or main bronchi. The results from this study support the hypothesis that trypsin activates a mechanism allowing for local release of sensory neurokinins from afferent C-fibers and that this release occurs independently of the sensory function of these nerves.

The role of endothelin in mediating virus-induced changes in endothelinB receptor density in mouse airways.

Emerging evidence supports a mediator role for endothelin (ET)-1 in airway diseases including asthma. Respiratory tract viral infections, are associated with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are causally linked, perhaps involving ET-1-induced ET(B) receptor downregulation, the current study investigated the influence of in vivo administration of CGS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET-content and ET(B) receptor density. CGS 26303 (5 mg x kg(-1) x day(-1)) or placebo was administered to mice via osmotic minipumps implanted subcutaneously. Two days after implantation, mice were inoculated with influenza A/PR-8/34 virus or sham-infected, and all measurements were performed on tissue obtained on the fourth day post-inoculation. Viral infection was associated with elevated levels of immunoreactive ET and decreased densities of ET(B) receptors in murine airways. Both of these effects were attenuated in virus-infected mice that had received CGS 26303. Virus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of infectious virus in the lungs and similarly, viral infection had no effect on the plasma levels of free CGS 26303. In summary, CGS 26303 inhibited the virus-induced changes in both immunoreactive endothelin content and endothelinB receptor density. These findings are consistent with the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelinB receptors in airway smooth muscle. Whether inhibitors of endothelin synthesis attenuate virus-induced exacerbations of asthma or airways hyperresponsiveness remains to be established.