The Early Youth Engagement (EYE-2) intervention in first-episode psychosis services: pragmatic cluster randomised controlled trial and cost-effectiveness evaluation.

Background: Early intervention in psychosis (EIP) services improve outcomes for young people, but approximately 30% disengage.

Aims: To test whether a new motivational engagement intervention would prolong engagement and whether it was cost-effective.

Method: We conducted a multicentre, single-blind, parallel-group, cluster randomised controlled trial involving 20 EIP teams at five UK National Health Service (NHS) sites.

Development and preliminary validation of a diagnostic prediction model to optimise outpatient management of patients with urolithiasis using urinary stones and intervention quality of life (USIQoL) measure.

Purpose: Patients with urinary calculi undergo resource-intensive follow-up. Application of a PROM, Urinary Stones and Intervention Quality of Life (USIQoL), can potentially optimise current practices if it matches the outcomes of traditional follow-up. Our objective was to develop, and conduct, a preliminary validation of the USIQoL based prediction model to aid triage.

Recruitment of Cdc48 to chloroplasts by a UBX-domain protein in chloroplast-associated protein degradation.

The translocon at the outer chloroplast membrane (TOC) is the gateway for chloroplast protein import and so is vital for photosynthetic establishment and plant growth. Chloroplast-associated protein degradation (CHLORAD) is a ubiquitin-dependent proteolytic system that regulates TOC. In CHLORAD, cytosolic Cdc48 provides motive force for the retrotranslocation of ubiquitinated TOC proteins to the cytosol but how Cdc48 is recruited is unknown.

Electrical Signaling Beyond Neurons.

Neural action potentials (APs) are difficult to interpret as signal encoders and/or computational primitives. Their relationships with stimuli and behaviors are obscured by the staggering complexity of nervous systems themselves. We can reduce this complexity by observing that "simpler" neuron-less organisms also transduce stimuli into transient electrical pulses that affect their behaviors.

Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner.

While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity.

Chloroplast protein translocation pathways and ubiquitin-dependent regulation at a glance.

Chloroplasts conduct photosynthesis and numerous metabolic and signalling processes that enable plant growth and development. Most of the ∼3000 proteins in chloroplasts are nucleus encoded and must be imported from the cytosol. Thus, the protein import machinery of the organelle (the TOC-TIC apparatus) is of fundamental importance for chloroplast biogenesis and operation.

Impact of the COVID-19 pandemic on antipsychotic prescribing in individuals with autism, dementia, learning disability, serious mental illness or living in a care home: a federated analysis of 59 million patients' primary care records in situ using OpenSAFELY.

Background: The COVID-19 pandemic affected how care was delivered to vulnerable patients, such as those with dementia or learning disability.

Objective: To explore whether this affected antipsychotic prescribing in at-risk populations.

Methods: With the approval of NHS England, we completed a retrospective cohort study, using the OpenSAFELY platform to explore primary care data of 59 million patients.

Disseminated urinary tract infection resulting in septic arthritis of the glenohumeral joint.

An 89-year-old male with a background of metastatic transitional cell carcinoma presented acutely with new hydronephrosis and deranged renal function secondary to high pressure chronic urinary retention. A recent urine culture was positive for (E.coli).

Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation.

Developing astroglia play important roles in regulating synaptogenesis through secreted and contact signals. Whether they regulate postnatal axon growth is unknown. By selectively isolating exosomes using size-exclusion chromatography (SEC) and employing cell-type specific exosome reporter mice, our current results define a secreted astroglial exosome pathway that can spread long-range in vivo and stimulate axon growth of cortical pyramidal neurons.

Environmental Public Health practice: designing and delivering a locally desirable service.

Objectives: We reviewed environmental public health practice at a local level (roles, responsibilities, interaction with partner agencies) to establish what and how an integrated approach to the service, as found in Cheshire and Merseyside, North West England, should be delivered, if at all, and at what footprint.

Study Design: Mixed methods approach.

Methods: We triangulated: qualitative interviews with relevant professionals to gain an in-depth understanding of their interest and vision for any health protection input to health risks and outcomes from environmental issues; an electronic questionnaire assessing experience, interest, vision and comfort zones of a wider range of professionals involved in environmental health issues; a half-day workshop to review study findings and agree ways forward.

Chronic nSMase inhibition suppresses neuronal exosome spreading and sex-specifically attenuates amyloid pathology in APP knock-in Alzheimer's disease mice.

Female biased pathology and cognitive decline in Alzheimer's disease (AD) have been consistently observed with unclear underlying mechanisms. Although brain sphingolipid ceramide is elevated in AD patients, whether and how ceramide may contribute to sex-specific differences in amyloid pathology is unknown. Here we investigated the sex-specific impact of chronic pharmacological inhibition of neutral sphingomyelinase (nSMase), a key enzyme responsible for ceramide metabolism, on in vivo neuron-derived exosome dynamics, Aβ plaque load, and cognitive function in the APP knock-in (APP NL-F) AD mouse model.

Changes in medication safety indicators in England throughout the covid-19 pandemic using OpenSAFELY: population based, retrospective cohort study of 57 million patients using federated analytics.

Objective: To implement complex, PINCER (pharmacist led information technology intervention) prescribing indicators, on a national scale with general practice data to describe the impact of the covid-19 pandemic on safe prescribing.

Design: Population based, retrospective cohort study using federated analytics.

Setting: Electronic general practice health record data from 56.

Selective autophagy regulates chloroplast protein import and promotes plant stress tolerance.

Chloroplasts are plant organelles responsible for photosynthesis and environmental sensing. Most chloroplast proteins are imported from the cytosol through the translocon at the outer envelope membrane of chloroplasts (TOC). Previous work has shown that TOC components are regulated by the ubiquitin-proteasome system (UPS) to control the chloroplast proteome, which is crucial for the organelle's function and plant development.

Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.

Hyperpolarizing GABAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl extrusion, a process that is facilitated by the neuronal specific K/Cl co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE).

Chloroplast Proteostasis: Import, Sorting, Ubiquitination, and Proteolysis.

Chloroplasts are the defining plant organelles with responsibility for photosynthesis and other vital functions. To deliver these functions, they possess a complex proteome comprising thousands of largely nucleus-encoded proteins. Composition of the proteome is controlled by diverse processes affecting protein translocation and degradation-our focus here.

Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation.

Developing astroglia play important roles in regulating synaptogenesis through secreted and contact signals. Whether they regulate postnatal axon growth is unknown. By selectively isolating exosomes using size-exclusion chromatography (SEC) and employing cell-type specific exosome reporter mice, our current results define a secreted astroglial exosome pathway that can spread long-range and stimulate axon growth of cortical pyramidal neurons.

Multiple ubiquitin E3 ligase genes antagonistically regulate chloroplast-associated protein degradation.

The chloroplast is the most prominent member of a diverse group of plant organelles called the plastids, and it is characterized by its vital role in photosynthesis. Most of the ∼3,000 different proteins in chloroplasts are synthesized in the cytosol in precursor (preprotein) form, each with a cleavable transit peptide. Preproteins are imported via translocons in the outer and inner envelope membranes of the chloroplast, termed TOC and TIC, respectively.

Nutritional Supplement and Dietary Interventions as a Prophylaxis or Treatment of Sub-Concussive Repetitive Head Impact and Mild Traumatic Brain Injury: A Systematic Review.

Mild traumatic brain injury (mTBI) affects 42 to 56 million individuals worldwide annually. Even more individuals are affected by sub-concussive repetitive head impacts (SRHIs). Such injuries may result in significant acute and chronic symptoms.

Ubiquitin-based pathway acts inside chloroplasts to regulate photosynthesis.

Photosynthesis is the energetic basis for most life on Earth, and in plants it operates inside double membrane-bound organelles called chloroplasts. The photosynthetic apparatus comprises numerous proteins encoded by the nuclear and organellar genomes. Maintenance of this apparatus requires the action of internal chloroplast proteases, but a role for the nucleocytosolic ubiquitin-proteasome system (UPS) was not expected, owing to the barrier presented by the double-membrane envelope.