Emergency Medical Services Response to Mass Shooting and Active Shooter Incidents, United States, 2014-2015.

BACKGROUND: The purpose of the current study was to describe the injury patterns, EMS response and interventions to mass shooting (MS) and active shooter (AS) incidents. METHODS: Retrospective analysis of 2014-2015 National Emergency Medical Services Information System (NEMSIS) data sets. Date, time, and location for MS incidents were obtained from the Gun Violence Archive and then correlated with NEMSIS data set records. AS incidents were identified through Federal Bureau of Investigation (FBI) data. A de-identified database was generated for final analysis. RESULTS: A total of 608 MS incidents were identified, of which 19 were also classified as AS incidents. NEMSIS patient care data was available for 652 EMS activations representing 226 unique MS incidents. Thirty-four EMS responses to 5 unique AS incidents were similarly identified: 76% of victims were male and 80% of victims were African American. Dispatch complaint did not suggest shooting (potentially dangerous scene environment) in 15.9% of records. The most commonly reported incident locations for MS were Street/Highway (38.2%) and Home/Residence (32.4%). Location of wounds included extremities (49%), chest (12%), and head/neck (13%). Tourniquet use was documented in 6 victims. 35.9% of victims were transported to the closest facility. CONCLUSIONS: MS and AS incidents are prevalent in the United States. Despite the fact that extremity wounds were common, documented EMS tourniquet use was uncommon. While MS events are high risk for responders, dispatch information was lacking in almost 15% of records. Responding EMS agencies were diverse, emphasizing the need to ensure all EMS providers are prepared to respond to MS incidents.

Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype.

X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype-phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies.

Are relative contraindications for unicompartmental knee replacements in medial compartment osteoarthritis really contraindications?

Background: Medial unicompartment knee replacement (UKR) is performed for isolated medial compartment osteoarthritis. Understanding the factors influencing functional outcomes helps patient selection and outcomes. We will review the association between pre-operative BMI and patellofemoral articular wear on post operative Oxford Knee Scores at >2 and > 5 years. Methods: A retrospective review of a prospectively collected database was performed. Inclusion criteria were medial UKR for medial compartment OA. The exclusion criteria were age <16, revision procedures and lateral UKR's. Data was collected between 26/6/2014 and 25/8/2022. Statistical analysis was performed using SPSS. Significance was given to variables that reached p < 0.05. Results: 159 UKR procedures were identified in 155 patients. 116 procedures carried out on 111 patients had follow up at > 2 years. At 5 years there were 14 patients had OKS recorded. There was no statistical difference in the ICRS grade I&II vs III&IV groups for >2 year or >5 year OKS with p = 0.408 and p = 0.876. For BMI there was a moderately negative correlation on spearman's rank p(df) = -0.339 (CI 95 % -0.538, -0.104) at >2 years, which was statistically significant with p = 0.004. >5 year data didn't reach significance with p = 0.828. Conclusion: BMI maybe an important patient factor in predicting post operative OKS at 2-5 years. This is beneficial to surgeons for patient selection in medial UKR. Patellofemoral wear doesn't appear to impact on post operative functional outcomes. This supports the theory that patient who suffer from patellofemoral wear, as well as medial compartment wear can benefit from UKR, expanding the current indications.

Tumour-specific phosphorylation of serine 419 drives alpha-enolase (ENO1) nuclear export in triple negative breast cancer progression.

BACKGROUND: The glycolytic enzyme alpha-enolase is a known biomarker of many cancers and involved in tumorigenic functions unrelated to its key role in glycolysis. Here, we show that expression of alpha-enolase correlates with subcellular localisation and tumorigenic status in the MCF10 triple negative breast cancer isogenic tumour progression model, where non-tumour cells show diffuse nucleocytoplasmic localisation of alpha-enolase, whereas tumorigenic cells show a predominantly cytoplasmic localisation. Alpha-enolase nucleocytoplasmic localisation may be regulated by tumour cell-specific phosphorylation at S419, previously reported in pancreatic cancer. RESULTS: Here we show ENO1 phosphorylation can also be observed in triple negative breast cancer patient samples and MCF10 tumour progression cell models. Furthermore, prevention of alpha-enolase-S419 phosphorylation by point mutation or a casein kinase-1 specific inhibitor D4476, induced tumour-specific nuclear accumulation of alpha-enolase, implicating S419 phosphorylation and casein kinase-1 in regulating subcellular localisation in tumour cell-specific fashion. Strikingly, alpha-enolase nuclear accumulation was induced in tumour cells by treatment with the specific exportin-1-mediated nuclear export inhibitor Leptomycin B. This suggests that S419 phosphorylation in tumour cells regulates alpha-enolase subcellular localisation by inducing its exportin-1-mediated nuclear export. Finally, as a first step to analyse the functional consequences of increased cytoplasmic alpha-enolase in tumour cells, we determined the alpha-enolase interactome in the absence/presence of D4476 treatment, with results suggesting clear differences with respect to interaction with cytoskeleton regulating proteins. CONCLUSIONS: The results suggest for the first time that tumour-specific S419 phosphorylation may contribute integrally to alpha-enolase cytoplasmic localisation, to facilitate alpha-enolase's role in modulating cytoskeletal organisation in triple negative breast cancer. This new information may be used for development of triple negative breast cancer specific therapeutics that target alpha-enolase.

Intraperitoneal seeding of a testicular mixed germ cell tumor following spontaneous intraperitoneal mass rupture with associated anti-NMDA paraneoplastic encephalitis.

A 25-year-old male was admitted to the neurological intensive care unit for neurologic deterioration, likely caused by a paraneoplastic syndrome secondary to testicular malignancy. He experienced spontaneous rupture and hemorrhage of his testicular mass arising from an undescended testis while admitted. The tumor was excised, revealing a mixed germ cell tumor. Serum tumor markers began to rise after 4 cycles of chemotherapy. Surveillance scans 32 weeks after mass rupture revealed numerous tumor deposits throughout his peritoneum concerning for teratoma. We review a case of intraperitoneal metastasis of a testicular mixed germ cell tumor following intra-abdominal mass rupture.

Internalized Functional DNA Aptamers as Alternative Cancer Therapies.

Despite major advances, cancer remains one of the largest burdens of disease worldwide. One reason behind this is that killing tumor cells without affecting healthy surrounding tissue remains a largely elusive prospect, despite the widespread availability of cytotoxic chemotherapeutic agents. To meet these modern healthcare requirements, it is essential to develop precision therapeutics that minimise off-target side-effects for various cancer types. To this end, highly specific molecular targeting agents against cancer are of great interest. These agents may work by targeting intracellular signalling pathways following receptor binding, or via internalization and targeting to specific subcellular compartments. DNA aptamers represent a promising molecular tool in this arena that can be used for both specific cell surface targeting and subsequent internalization and can also elicit a functional effect upon internalization. This review examines various cancer targeting cell-internalizing aptamers, with a particular focus towards functional aptamers that do not require additional conjugation to nanoparticles or small molecules to elicit a biological response. With a deeper understanding and precise exploitation of cancer specific molecular pathways, functional intracellular DNA aptamers may be a powerful step towards more widespread development of precision therapeutics.

Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models.

Myotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ) transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.