Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex.

Breathing behaviour involves the generation of normal breaths (eupnoea) on a timescale of seconds and sigh breaths on the order of minutes. Both rhythms emerge in tandem from a single brainstem site, but whether and how a single cell population can generate two disparate rhythms remains unclear. We posit that recurrent synaptic excitation in concert with synaptic depression and cellular refractoriness gives rise to the eupnoea rhythm, whereas an intracellular calcium oscillation that is slower by orders of magnitude gives rise to the sigh rhythm. A mathematical model capturing these dynamics simultaneously generates eupnoea and sigh rhythms with disparate frequencies, which can be separately regulated by physiological parameters. We experimentally validated key model predictions regarding intracellular calcium signalling. All vertebrate brains feature a network oscillator that drives the breathing pump for regular respiration. However, in air-breathing mammals with compliant lungs susceptible to collapse, the breathing rhythmogenic network may have refashioned ubiquitous intracellular signalling systems to produce a second slower rhythm (for sighs) that prevents atelectasis without impeding eupnoea. KEY POINTS: A simplified activity-based model of the preBötC generates inspiratory and sigh rhythms from a single neuron population. Inspiration is attributable to a canonical excitatory network oscillator mechanism. Sigh emerges from intracellular calcium signalling. The model predicts that perturbations of calcium uptake and release across the endoplasmic reticulum counterintuitively accelerate and decelerate sigh rhythmicity, respectively, which was experimentally validated. Vertebrate evolution may have adapted existing intracellular signalling mechanisms to produce slow oscillations needed to optimize pulmonary function in mammals.

Meta-analysis of clinical risk factors for suicide among people presenting to emergency departments and general hospitals with suicidal thoughts and behaviours.

BACKGROUND: Suicidal thoughts and behaviours (STB) are a common reason for presentation to emergency departments and general hospitals. A meta-analysis of the strength of clinical risk factors for subsequent suicide might aid understanding of suicidal behaviour and help suicide prevention. METHODS: We conducted a meta-analysis of cohort and controlled studies on clinical risk factors and later suicide among people presenting to emergency departments and general hospitals with STB. Data were extracted from papers meeting inclusion criteria, published in Medline, PsycINFO, and Embase between 1 January 1960 and 10 October 2022 using papers located with the search terms ((suicide*).m_titl AND (emergency* OR accident and emergency OR casualty OR general hospital OR toxicology service).mp) or were indexed in PubMed and had titles located with the search terms (suicide* OR self-harm OR self-harm OR self-injury OR self-injury OR self-poisoning OR self-poisoning OR overdose OR para-suicide OR parasuicide [title/abstract]) AND (Emergency department OR emergency room OR Casualty OR general hospital OR toxicology OR accident and emergency [all fields]). Data about the association between clinical risk factors and suicide extracted from three or more studies were included in a random-effects meta-analysis of the odds of later death by suicide. The study was registered in PROSPERO and conducted according to MOOSE and PRISMA guidelines. RESULTS: Seventy-five studies reported on 741,624 people, of which 19,649 died by suicide (2.65%). Male sex (odds ratio (OR) = 1.99) and age (OR = 2.01) were the most consistently reported risk factors. The strongest associations with subsequent death by suicide related to violent self-harm methods at the hospital presentation, including: unspecified violent method (OR = 4.97), any violent method (OR = 4.57) and the specific violent methods of drowning (OR = 4.32), hanging (OR = 4.26), and use of firearms (OR = 10.08). Patients categorised as higher risk using suicide prediction scales or any other method that combined risk factors had moderately increased odds of suicide (OR = 2.58). Younger age, Black and Hispanic ethnicity, overdose, a diagnosis of adjustment disorder, and the absence of any psychiatric diagnosis were protective against suicide. CONCLUSIONS: Most risk factors for suicide among people who have presented with STB are not strongly associated with later suicide. The strongest risk factors relate to self-harm methods. In the absence of clear indicators of future suicide, all people presenting with suicidality warrant a thorough assessment of their needs, and further research is needed before we can meaningfully categorise people with STB according to suicide risk.

Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na+ current (INaP) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking down the Scn8a (Nav1.6 [voltage-gated sodium channel 1.6]) gene in core rhythmogenic preBötC neurons. Deleting Scn8a substantially decreases the INaP and abolishes bursting-pacemaker activity, which slows inspiratory rhythm in vitro and negatively impacts the postnatal development of ventilation. Diminishing Scn8a via genetic interference has no impact on breathing in adult mice. We argue that the Scn8a-mediated INaP is not obligatory but that it influences the development and rhythmic function of the preBötC. The ubiquity of the INaP in respiratory brainstem interneurons could underlie breathing-related behaviors such as neonatal phonation or rhythmogenesis in different physiological conditions.

A survey of Australian psychiatrists' and psychiatry trainees' knowledge of and attitudes towards psychedelics in the treatment of psychiatric disorders.

OBJECTIVE: To assess Australian psychiatrists' and psychiatry trainees' knowledge of and attitudes towards psychedelics as treatment for psychiatric disorders. METHOD: Australian members of the Royal Australian and New Zealand College of Psychiatrists were invited to participate in an anonymous survey that ran from October 1 to November 30 2021. Participants were asked about their knowledge of the risks and benefits of, and attitudes towards, psychedelics, including the factors that influence those attitudes. RESULTS: Fifty-one doctors responded to the survey, and 38 completed all items. The majority were male, consultants and based primarily in New South Wales. Respondents reported awareness of the evidence demonstrating the benefits of psychedelics for most disorders; however most respondents, particularly females, perceived psychedelics as risky. Most considered themselves open-minded and believed psychedelics deserved further research. CONCLUSIONS: The poor response rate was a major limitation of this study. Our sample of Australian psychiatrists and trainees were enthusiastic about psychedelics as psychiatric treatment and were aware of some of the evidence demonstrating their efficacy. Safety continues to be a concern, despite growing evidence of their safety in therapeutic settings. Education about the evidence of their efficacy and the risks associated with their use is needed.

Role of Synaptic Inhibition in the Coupling of the Respiratory Rhythms that Underlie Eupnea and Sigh Behaviors.

The preBötzinger complex (preBötC) gives rise to two types of breathing behavior under normal physiological conditions: eupnea and sighing. Here, we examine the neural mechanisms that couple their underlying rhythms. We measured breathing in awake intact adult mice and recorded inspiratory rhythms from the preBötC in neonatal mouse brainstem slice preparations. We show previously undocumented variability in the temporal relationship between sigh breaths or bursts and their preceding eupneic breaths or inspiratory bursts. Investigating the synaptic mechanisms for this variability in vitro, we further show that pharmacological blockade of chloride-mediated synaptic inhibition strengthens inspiratory-to-sigh temporal coupling. These findings contrast with previous literature, which suggested glycinergic inhibition linked sigh bursts to their preceding inspiratory bursts with minimal time intervals. Furthermore, we verify that pharmacological disinhibition did not alter the duration of the prolonged interval that follows a sigh burst before resumption of the inspiratory rhythm. These results demonstrate that synaptic inhibition does not enhance coupling between sighs and preceding inspiratory events or contribute to post-sigh apneas. Instead, we conclude that excitatory synaptic mechanisms coordinate inspiratory (eupnea) and sigh rhythms.

Evaluating the Burstlet Theory of Inspiratory Rhythm and Pattern Generation.

The preBötzinger complex (preBötC) generates the rhythm and rudimentary motor pattern for inspiratory breathing movements. Here, we test "burstlet" theory (Kam et al., 2013a), which posits that low amplitude burstlets, subthreshold from the standpoint of inspiratory bursts, reflect the fundamental oscillator of the preBötC. In turn, a discrete suprathreshold process transforms burstlets into full amplitude inspiratory bursts that drive motor output, measurable via hypoglossal nerve (XII) discharge in vitro We recap observations by Kam and Feldman in neonatal mouse slice preparations: field recordings from preBötC demonstrate bursts and concurrent XII motor output intermingled with lower amplitude burstlets that do not produce XII motor output. Manipulations of excitability affect the relative prevalence of bursts and burstlets and modulate their frequency. Whole-cell and photonic recordings of preBötC neurons suggest that burstlets involve inconstant subsets of rhythmogenic interneurons. We conclude that discrete rhythm- and pattern-generating mechanisms coexist in the preBötC and that burstlets reflect its fundamental rhythmogenic nature.

Vitamin K deficiency bleeding in Australian infants 1993-2017: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To undertake surveillance of vitamin K deficiency bleeding (VKDB) in Australia from 1993 to 2017, during a time of change to national recommendations and available vitamin K formulations. METHODS: Paediatricians reported cases of VKDB in infants aged <6 months and provided demographic, clinical and biochemical information via the Australian Paediatric Surveillance Unit. RESULTS: 58 cases were reported, of which 5 (9%) were early, 11 (19%) classic and 42 (72%) late VKDB. 53 (91%) were exclusively breast fed. Seven (12%) received oral prophylaxis, the majority (86%) of whom did not receive all three recommended doses. The overall reported incidence was 0.84 per 100 000 live births (95% CI: 0.64 to 1.08) and the incidence of late VKDB was 0.61 per 100 000 live births (95% CI: 0.44 to 0.82), which are similar to rates reported by other countries where intramuscular vitamin K is recommended. VKDB rates were significantly higher (2.46 per 100 000 live births; 95% CI: 1.06 to 4.85) between 1993 and March 1994 when oral prophylaxis was recommended (p<0.05). Vitamin K was not given to 33 (57%) cases, primarily due to parental refusal, and the number of parental refusals increased significantly after 2006 (p<0.05). There were six deaths, all due to intracranial haemorrhage, and three associated with home delivery and parental refusal of vitamin K. CONCLUSIONS: Incidence rates of VKDB in Australia are among the lowest in the world; however, we have identified an increasing trend of parental refusal. Ongoing surveillance and educational campaigns for health professionals and parents are needed to prevent VKDB.

Ionic versus metallic bonding in AlnNam and AlnMgm (m ≤ 3, n + m ≤ 15) clusters.

First principles electronic structure studies on the ground state geometries, stability, and the electronic structure of AlnNam and AlnMgm (m ≤ 3, n + m ≤ 15) clusters have been carried out to examine the nature of bonding between Na or Mg and Al. Identifying whether the bonding is ionic or metallic in bulk materials is typically straightforward; however, in small clusters where quantum confinement is important, the nature of bonding may become unclear. We have performed a critical analysis of the bonding in these bimetallic clusters using charge analysis, electrical dipole moments, hybridization of the atomic orbitals, the Laplacian of the charge density at the bond critical points, and the change in the bonding energy between neutral and anionic forms of the cluster. For NanAlm clusters, we find that the Na binding is primarily ionic, while the bonding in AlnMgm is primarily metallic. We find that the Mulliken population of the 3p orbital of Na and Mg can provide a rapid assessment of the nature of bonding. We also find that the Hirshfeld charge and dipole moments are effective indicators, when placed in context. We found that the Laplacian of the charge density at the bond critical points can be misleading in identifying whether the bonding is ionic or metallic in small clusters.

Probing the magic numbers of aluminum-magnesium cluster anions and their reactivity toward oxygen.

We report a joint experimental and theoretical investigation into the geometry, stability, and reactivity with oxygen of alloy metal clusters Al(n)Mg(m)(-) (4 ≤ n+m ≤ 15; 0 ≤ m ≤ 3). Considering that Al and Mg possess three and two valence electrons, respectively, clusters with all possible valence electron counts from 11 to 46 are studied to probe the magic numbers predicted by the spherical jellium model, and to determine whether enhanced stability and reduced reactivity may be found for some Al(n)Mg(m)(-) at non-magic numbers. Al5Mg2(-) and Al11Mg3(-) exhibit enhanced stability corresponding to the expected magic numbers of 20 and 40 electrons, respectively; while Al7Mg3(-), Al11Mg(-), and Al11Mg2(-) turn out to be unexpectedly stable at electron counts of 28, 36, and 38, respectively. The enhanced stability at non-magic numbers is explained through a crystal-field-like splitting of degenerate shells by the geometrical distortions of the clusters. Al(n)Mg(m)(-) clusters appear to display higher oxidation than pure Al(n)(-) clusters, suggesting that the addition of Mg atoms enhances the combustion of pure aluminum clusters.