Expanding the mutational spectrum of LZTR1 in schwannomatosis

Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.     

Potential utility of bone scan in cranial bone flap osteomyelitis

Annals of Nuclear Medicine - Currently, the diagnosis of bone flap osteomyelitis (BFO) remains a challenge for medical imaging. The present study aimed to identify predictive scintigraphic patterns...     

Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone

Mycolactone is a polyketide toxin produced by Mycobacterium ulcerans (Mu), the causative agent of the skin disease Buruli ulcer (BU). Surprisingly, infected tissues lack inflammatory infiltrates. Structural similarities between mycolactone and immunosuppressive agents led us to investigate the immunomodulatory properties of mycolactone on dendritic cells (DCs), the key initiators and regulators of immune responses. At noncytotoxic concentrations, phenotypic and functional maturation of both mouse and human DCs was inhibited by mycolactone. Notably, mycolactone blocked the emigration of mouse-skin DCs to draining lymph nodes, as well as their maturation in vivo. In human peripheral blood-derived DCs, mycolactone inhibited the ability to activate allogeneic T cell priming and to produce inflammatory molecules. Interestingly, production of the cytokines interleukin (IL) 12, tumor necrosis factor alpha, and IL-6 was only marginally affected, whereas production of the chemokines macrophage inflammatory protein (MIP) 1alpha, MIP-1beta, regulated on activation, normal T cell expressed and secreted, interferon gamma-inducible protein 10, and monocyte chemoattractant protein 1 was abolished at nanomolar concentrations. Importantly, mycolactone endogenously expressed by Mu mediated similar inhibitory effects on beta-chemokine production by DCs. In accordance with the histopathological features of BUs, our results suggest that bacterial production of mycolactone may limit both the initiation of primary immune responses and the recruitment of inflammatory cells to the infection site. Moreover, they highlight a potential interest in mycolactone as a novel immunosuppressive agent.     

A Team-Based Approach to Introduce and Sustain the Use of the WHO Surgical Safety Checklist in Tanzania

Introduction

Millions of patients worldwide suffer disability and death due to complications related to surgery. Many of these complications can be reduced by the use of the World Health Organization (WHO) Surgical Safety Checklist (SSC), a simple tool that can enhance teamwork and communication and improve patient safety. Despite the evidence on benefits of its use, introducing and sustaining the use of the checklist are challenging. We present a team-based approach employed in a low-resource setting in Tanzania, which resulted in high checklist utilization and compliance rates.

Methods

We reviewed reported data from facility registers supplemented by direct observation data by mentors to evaluate the use of the WHO SSC across 40 health facilities in two regions of Tanzania between January and December 2018. We analyzed the self-reported monthly data on total number of major surgeries performed and proportion of surgeries where the checklist was used. We also analyzed the use of the SSC during direct observation by external mentors and completion rates of the SSC in a random selection of patient files during two mentorship visits between June and December 2018.

Results

During the review period, the average self-reported checklist utilization rate was 79.3% (11,564 out of 14,580 major surgeries). SSC utilization increased from 0% at baseline in January 2018 to 98% in December 2018. The proportion of checklists that were completely and correctly filled out increased between the two mentor visits from 82.1 to 92.8%, but the gain was significantly greater at health centers than at hospitals (p < 0.05). Health centers (which had one or two surgical teams) self-reported a higher checklist utilization rate than hospitals (which had multiple surgical teams), i.e., 99.4% vs 68.8% (p < 0.05).

Conclusion and recommendations

Our findings suggest that Surgical Safety Checklist implementation is feasible even in lower-resource settings. The self-reported SSC utilization rate is higher than reported in other similar settings. We attribute this finding to the team-based approach employed and the ongoing regular mentorship. We recommend use of this approach to scale-up checklist use in other regions in the country as recommended in the Ministry of Health of Tanzania’s National Surgical, Obstetric, and Anesthesia Plan (NSOAP).