Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.

Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce their contact with synapses prior to microglia-mediated synapse engulfment. We further show that reduced astrocyte-contact with synapses is dependent on microglial CX3CL1-CX3CR1 signaling and release of Wnts from microglia following whisker removal. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, which then provides a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and this signaling is upregulated in several disease contexts.

A comparative analysis of microglial inducible Cre lines.

Cre/loxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. Microglial biology has particularly benefited because microglia historically have been difficult to transduce with virus or electroporation methods for gene delivery. Here, we investigate five of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency, cell-type specificity, and spontaneous recombination, depending on the Cre line and inter-loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency, particularly in microglia. There is increasing evidence that microglia are key regulators of neural circuits and major drivers of a broad range of neurological diseases. Reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field and the development of microglia-based therapeutics.

Reducing missed psychotherapy appointments: An advanced practice nurse-initiated telephone orientation protocol.

PURPOSE: Missed appointments pose significant challenges to the health care system as they contribute to the inefficient use of resources, increase costs, and result in poor outcomes. The aim of this project was to reduce the rate of missed adult psychotherapy appointments by implementing a Psychiatric-Mental Health Nurse Practitioner-initiated telephone orientation protocol (TOP). DESIGN: Quasi-experimental. METHODS: The TOP intervention combined an attendance policy review, psychoeducation, and motivational interviewing techniques. Missed appointment rates were compared before and after initiation of the TOP. FINDINGS: The TOP significantly reduced the rates of missed appointments by 55% over 12 weeks. PRACTICE IMPLICATIONS: The TOP can be implemented as standard care to increase client engagement, improve appointment attendance, and boost clinician productivity.

Lichen Planus Pemphigoides Associated With PD-1 and PD-L1 Inhibitors: A Case Series and Review of the Literature.

ABSTRACT: Immune checkpoint inhibitors are increasingly being used in the treatment of various solid organ and hematologic malignancies. Dermatologic toxicities associated with programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) therapy have been widely reported in the literature. It is important for clinicians to be aware of these toxicities to ensure prompt recognition and treatment. Herein, we present the clinical, histopathologic, and immunofluorescence findings of 3 patients diagnosed with lichen planus pemphigoides (LPP) after treatment with anti-PD-1 inhibitors. We also reviewed the literature and summarize 7 previously reported cases of LPP associated with anti-PD-1 and anti-PD-L1 inhibitors. LPP was diagnosed at a median time of 24.4 weeks (range: 4-78 weeks) after initiation of immunotherapy. Clinical findings included papules, plaques, erosions, vesicles, and bullae on the trunk and extremities. Oral involvement was present in half the cases. Histopathologic features of immunotherapy-induced LPP included lichenoid or vacuolar interface dermatitis, the presence of eosinophils, and subepidermal bullae. Direct immunofluorescence demonstrated linear deposition of immunoglobulin G (IgG) or C3. Indirect immunofluorescence demonstrated linear IgG along basement membrane zone on monkey esophagus in 2 cases and linear IgG on the epidermal side of salt split skin in 3 cases. Serum anti-BP180 was elevated in all cases in which enzyme-linked immunosorbent assay was performed.

Invasive Group B Streptococcus Disease With Recurrence and in Multiples: Towards a Better Understanding of GBS Late-Onset Sepsis.

Group B Streptococcus (GBS) is a common intestinal colonizer during the neonatal period, but also may cause late-onset sepsis or meningitis in up to 0.5% of otherwise healthy colonized infants after day 3 of life. Transmission routes and risk factors of this late-onset form of invasive GBS disease (iGBS) are not fully understood. Cases of iGBS with recurrence (n=25) and those occurring in parallel in twins/triplets (n=32) from the UK and Ireland (national surveillance study 2014/15) and from Germany and Switzerland (retrospective case collection) were analyzed to unravel shared (in affected multiples) or fixed (in recurrent disease) risk factors for GBS disease. The risk of iGBS among infants from multiple births was high (17%), if one infant had already developed GBS disease. The interval of onset of iGBS between siblings was 4.5 days and in recurrent cases 12.5 days. Disturbances of the individual microbiome, including persistence of infectious foci are suggested e.g. by high usage of perinatal antibiotics in mothers of affected multiples, and by the association of an increased risk of recurrence with a short term of antibiotics [aOR 4.2 (1.3-14.2), P=0.02]. Identical GBS serotypes in both recurrent infections and concurrently infected multiples might indicate a failed microbiome integration of GBS strains that are generally regarded as commensals in healthy infants. The dynamics of recurrent GBS infections or concurrent infections in multiples suggest individual patterns of exposure and fluctuations in host immunity, causing failure of natural niche occupation.

Drug Reaction with Eosinophilia and Systemic Syndrome in Revision Arthroplasty for a Prosthetic Knee Infection: A Case Report.

CASE: A 51-year-old woman underwent stage I of a 2-stage revision for a prosthetic knee infection with a vancomycin-impregnated articulating cement spacer followed by IV vancomycin and ceftriaxone. Four weeks later, she developed fevers, a diffuse cutaneous eruption, lymphadenopathy, transaminitis, and acute renal tubular necrosis before being diagnosed with drug reaction with eosinophilia and systemic syndrome (DRESS). CONCLUSION: DRESS is a rare, potentially life-threatening adverse drug reaction with cutaneous manifestations and multiorgan involvement. Although rare, its incidence in orthopaedic patients is likely to increase with the aging population. It must be recognized early to minimize end-stage organ dysfunction and mortality.

Group B streptococcal disease in UK and Irish infants younger than 90 days, 2014-15: a prospective surveillance study.

BACKGROUND: Group B streptococcus is a leading cause of serious infection in young infants in many countries worldwide. We aimed to define the burden and clinical features of invasive group B streptococcal disease in infants younger than 90 days in the UK and Ireland, together with the characteristics of disease-causing isolates. METHODS: Prospective, active national surveillance of invasive group B streptococcal disease in infants younger than 90 days was done from April 1, 2014, to April 30, 2015, through the British Paediatric Surveillance Unit, microbiology reference laboratories, and national public health agencies in the UK and Ireland. Early onset was defined as disease in the first 6 days of life and late onset was defined as 7-89 days of life. Incidence was calculated using livebirths in 2014 (after adjustment for the 13-month surveillance period). Isolates were characterised by serotyping, multilocus sequence typing, and antimicrobial susceptibility testing. FINDINGS: 856 cases of group B streptococcus were identified in 2014-15, an incidence of 0·94 per 1000 livebirths (95% CI 0·88-1·00). Incidence for early-onset disease (n=517) was 0·57 per 1000 livebirths (95% CI 0·52-0·62), and for late-onset disease (n=339) was 0·37 per 1000 livebirths (0·33-0·41). 53 infants died (case fatality rate 6·2%), of whom 27 had early-onset disease (case fatality rate 5·2%) and 26 had late-onset disease (case fatality rate 7·7%). The predominant serotypes were III (241 [60%] of 402 serotyped isolates) and Ia (69 [17%]); five serotypes (Ia, Ib, II, III, V) accounted for 377 (94%) of all serotyped isolates. INTERPRETATION: The incidence of invasive infant group B streptococcal disease in the UK and Ireland has increased since a comparable study done in 2000-01. The burden of early-onset disease has not declined despite the introduction of national prevention guidelines. New strategies for prevention are required. FUNDING: Meningitis Now.