Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory

Colorectal cancer cell line proteomes are representative of primary tumors and predict drug sensitivity

Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses. Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data. Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post-transcriptional regulation were recapitulated in cell lines. The 5 proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling, and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses. Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking

Decreased reward-seeking, often called anhedonia, forms a core symptom of depression. Often, decreased reward-seeking appears as impaired reward anticipation. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. To determine how stress alters neural communication, we recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) local field potential (LFP) that predicts the degree of subsequent blunted reward-seeking. This 4 Hz oscillation exhibited strong coherence between the ventral tegmental area (VTA) and the NAc. Through pharmacological inhibition of the VTA, we found that VTA neural activity is necessary for the generation of the 4 Hz oscillation, and extracellular recordings of multi-unit activity in the VTA reveal that VTA neural activity leads the phase of the 4 Hz NAc oscillation. We used transgenic mouse lines to selectively express the inhibitory opsin Archaerhodopsin in dopamine (DA), GABA, and glutamate neurons in the VTA. We combined cell type specific optogenetic inhibition with extracellular single-unit recordings in the VTA and LFP recordings in the NAc to identify the phase-locking of specific cell type spiking with the NAc4 Hz oscillation, as well as to identify the extent to which VTA populations contribute to the generation of the 4 Hz NAc oscillation. We found that VTA GABA neuron firing leads the phase of the 4 Hz NAc oscillation, and that VTA GABA activity is necessary for the generation of the 4 Hz NAc oscillation. This result led us to determine whether rhythmic VTA GABA activity contributes to stress-induced anhedonia. Surprisingly, while previous studies on blunted reward-seeking focused on DA transmission from the VTA to the NAc, we found that VTA GABA neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons during stress disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz in the absence of stress reproduces both oscillations and blunted reward-seeking. Finally, we found that stress disrupts VTA GABA, but not VTA DA, neural encoding of reward anticipation. Thus, stress elicits rhythmic VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking

North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations Part II: Topical, intralesional, and systemic medical management

Hidradenitis suppurativa is a severe and debilitating dermatologic disease. Clinical management is challenging and consists of both medical and surgical approaches, which must often be combined for best outcomes. Therapeutic approaches have evolved rapidly in the last decade and include the use of topical therapies, systemic antibiotics, hormonal therapies, and a wide range of immunomodulating medications. An evidence-based guideline is presented to support health care practitioners as they select optimal medical management strategies and is reviewed in this second part of the management guidelines. A therapeutic algorithm informed by the evidence available at the time of the review is provided

North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations Part I: Diagnosis, evaluation, and the use of complementary and procedural management

Hidradenitis suppurativa is a chronic inflammatory disorder affecting hair follicles, with profoundly negative impact on patient quality of life. Evidence informing ideal evaluation and management of patients with hidradenitis suppurativa is still sparse in many areas, but it has grown substantially in the last decade. Part I of this evidence-based guideline is presented to support health care practitioners as they select optimal management strategies, including diagnostic testing, comorbidity screening, and both complementary and procedural treatment options. Recommendations and evidence grading based on the evidence available at the time of the review are provided

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms

Introduction Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates.Methods and analysis The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study’s aims.Ethics and dissemination Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals.Trial registration number ISRCTN17658526