Parental risk factors and children entering out-of-home care: The effects of cumulative risk and parent's sex

Background Parental difficulties, including mental ill health, substance misuse, domestic violence and learning disability have been associated with children entering out-of-home care. There is also evidence that these issues may co-occur within families. Understanding how the co-occurrence of these difficulties is associated with care entry is complex because they may co-occur in the same or different household members and have different impacts on the likelihood of care entry when they occur in mothers, fathers or in single parent households. Method Administrative data from local authority children’s services in Wales were linked with demographic data to identify households in which children lived prior to entering care. Linkage to birth data identified biological mothers. Linkage with primary care, emergency department, hospital admissions and substance misuse services data enabled indicators of substance misuse, mental health, assaults in the home, learning disability and neurodivergence in the adults in those households to be identified. A series of multilevel binary logistic regression models were used to explore the odds of a household having one or more children entering care if risk factors were present. These considered the effects of individual risks, and cumulative risk both in individual adults in the household, and across the whole household. The effects of the number of adults, having adults with no risks and the differential impacts of risks in biological mothers, other women or men were also explored. Additional models explored these factors in single adult households. Results Cumulative risks increased the likelihood of care entry, however this effect disappeared when individual risks were controlled for. The presence of an individual with no risks in the household acted as a protective factor. Overall, the impact of the risks on the odds of care entry was substantially greater if the risks were present in the biological mother than if they occurred in other adults (men or women) in the household. In single adult households risk factors had a much greater impact when they occurred in households headed by women as opposed to men. Conclusion Substantial differences in the effects of risk factors in female and male adults are apparent and further research is needed to understand why this is occurring to ensure that parents are treated equally in terms of support and statutory intervention regardless of their sex

Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN(VIP)) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN(VIP) neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN(VIP) neurons may regulate LMA rhythms. In vivo photometry revealed that while SCN(VIP) neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCN(VIP) neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCN(VIP) neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCN(VIP) cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCN(VIP) subtypes

High-Redshift Galaxy Candidates at z=9−13z = 9-13 as Revealed by JWST Observations of WHL0137-08

JWST was designed to peer into the distant universe and study galaxies nearer the beginning of time than previously. Here we report the discovery of 12 galaxy candidates observed 300-600 Myr after the Big Bang with photometric redshifts between z ~ 8.5-13 measured using JWST NIRCam imaging of the galaxy cluster WHL0137 observed in 8 filters spanning 0.8-5.0 $\mu$m, plus 9 HST filters spanning 0.4-1.7 $\mu$m. Three of these candidates are gravitationally lensed by the foreground galaxy cluster and have magnifications of $\mu \sim 3 - 8$. The remaining nine candidates are located in a second JWST NIRCam module, centered ~29' from the cluster center, with expected magnifications of $\mu$ <~ 1.1. Our sample of high-redshift candidates have observed F200W AB magnitudes between 25.9 and 28.1 mag and intrinsic F200W AB magnitudes between 26.4 and 29.7 mag ($M_{UV}$ = -22.5 to -17). We find the stellar masses of these galaxies are in the range $\log M_{*}/M_{\odot}$ = 8 - 9, and down to 7.5 for the lensed galaxies. All are young with mass-weighted ages < 100 Myr, low dust content $A_V$ < 0.15 mag, and high specific star formation rates sSFR ~10-50 Gyr$^{-1}$ for most. One z ~ 9 candidate is consistent with an age < 5 Myr and a sSFR ~250 Gyr$^{-1}$, as inferred from a strong F444W excess, implying [OIII]+H-beta rest-frame equivalent width ~2000 Angstrom, although an older and redder z~ 10 object is also allowed. Another z~9 candidate ID9356 is lensed into an arc 2.6" long by the effects of strong gravitational lensing ($\mu$~8), and has at least two bright knots of unevenly distributed star formation. This arc is the most spatially-resolved galaxy at z~9 known to date, revealing structures ~30 pc across. Follow-up spectroscopy of WHL0137 with JWST/NIRSpec is planned for later this year, which will validate some of these candidates and study their physical properties in more detail.Comment: submitted to Ap

The Retinoic Acid Receptor Agonist Am80 Increases Mucosal Inflammation in an IL-6 Dependent Manner During Trichuris muris Infection

PURPOSE: Vitamin A metabolites, such as all-trans-retinoic acid (RA) that act through the nuclear receptor; retinoic acid receptor (RAR), have been shown to polarise T cells towards Th2, and to be important in resistance to helminth infections. Co-incidentally, people harbouring intestinal parasites are often supplemented with vitamin A, as both vitamin A deficiency and parasite infections often occur in the same regions of the globe. However, the impact of vitamin A supplementation on gut inflammation caused by intestinal parasites is not yet completely understood. METHODS: Here, we use Trichuris muris, a helminth parasite that buries into the large intestine of mice causing mucosal inflammation, as a model of both human Trichuriasis and IBD, treat with an RARα/β agonist (Am80) and quantify the ensuing pathological changes in the gut. RESULTS: Critically, we show, for the first time, that rather than playing an anti-inflammatory role, Am80 actually exacerbates helminth-driven inflammation, demonstrated by an increased colonic crypt length and a significant CD4(+) T cell infiltrate. Further, we established that the Am80-driven crypt hyperplasia and CD4(+) T cell infiltrate were dependent on IL-6, as both were absent in Am80-treated IL-6 knock-out mice. CONCLUSIONS: This study presents novel data showing a pro-inflammatory role of RAR ligands in T. muris infection, and implies an undesirable effect for the administration of vitamin A during chronic helminth infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-013-9936-8) contains supplementary material, which is available to authorized users

A Novel Population of Wake-Promoting GABAergic Neurons in the Ventral Lateral Hypothalamus.

The largest synaptic input to the sleep-promoting ventrolateral preoptic area (VLPO) [1] arises from the lateral hypothalamus [2], a brain area associated with arousal [3-5]. However, the neurochemical identity of the majority of these VLPO-projecting neurons within the lateral hypothalamus (LH), as well as their function in the arousal network, remains unknown. Herein we describe a population of VLPO-projecting neurons in the LH that express the vesicular GABA transporter (VGAT; a marker for GABA-releasing neurons). In addition to the VLPO, these neurons also project to several other established sleep and arousal nodes, including the tuberomammillary nucleus, ventral periaqueductal gray, and locus coeruleus. Selective and acute chemogenetic activation of LH VGAT(+) neurons was profoundly wake promoting, whereas acute inhibition increased sleep. Because of its direct and massive inputs to the VLPO, this population may play a particularly important role in sleep-wake switching

Selective activation of serotoninergic dorsal raphe neurons facilitates sleep through anxiolysis.

A role for the brain's serotoninergic (5HT) system in the regulation of sleep and wakefulness has been long suggested. Yet, previous studies employing pharmacological, lesion and genetically driven approaches have produced inconsistent findings, leaving 5HT's role in sleep-wake regulation incompletely understood. Here we sought to define the specific contribution of 5HT neurons within the dorsal raphe nucleus (DRN5HT) to sleep and arousal control. To do this, we employed a chemogenetic strategy to selectively and acutely activate DRN5HT neurons and monitored sleep-wake using electroencephalogram recordings. We additionally assessed indices of anxiety using the open field and elevated plus maze behavioral tests and employed telemetric-based recordings to test effects of acute DRN5HT activation on body temperature and locomotor activity. Our findings indicate that the DRN5HT cell population may not modulate sleep-wake per se, but rather that its activation has apparent anxiolytic properties, suggesting the more nuanced view that DRN5HT neurons are sleep permissive under circumstances that produce anxiety or stress

Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are&nbsp;expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2

A hypothalamic circuit for the circadian control of aggression

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ(GABA)) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ(GABA) neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ(GABA) transmission phase-dependently increases aggression. Finally, SPZ(GABA)-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease