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BackgroundTraumatic spinal injury (TSI) is a disease of significant global health burden, particularly in low and middle-income countries where road traffic-related trauma is increasing. This study compared the demographics, injury patterns, and outcomes of TSI caused by road traffic accidents (RTAs) to non-traffic related TSI.MethodsA retrospective analysis was conducted using a neurotrauma registry from the Muhimbili Orthopaedic Institute (MOI) in Tanzania, a national referral center for spinal injuries. Patient sociodemographic characteristics, injury level, and severity were compared across mechanisms of injury. Neurological improvement, neurological deterioration, and mortality were compared between those sustaining TSI through an RTA versus non-RTA, using univariable and multivariable analyses.ResultsA total of 626 patients were included, of which 302 (48%) were RTA-related. The median age was 34 years, and 532 (85%) were male. RTAs had a lower male preponderance compared to non-RTA causes (238/302, 79% vs. 294/324, 91%, pConclusionOur study in urban Tanzania finds no significant differences in outcomes between spinal injuries from road traffic accidents (RTAs) and non-RTA causes, suggesting the need for equitable resource allocation in spine trauma programs. Highlighting the critical link between cervical injuries and increased mortality, our findings call for targeted interventions across all causes of traumatic spinal injuries (TSI). We advocate for a comprehensive trauma care system that merges efficient pre-hospital care, specialized treatment, and prevention measures, aiming to enhance outcomes and ensure equity in trauma care in low- and middle-income countries.

BackgroundMotor neurone disease (MND) is a rare neurodegenerative condition, with poorly understood aetiology. Large, population-based, prospective cohorts will enable powerful studies of the determinants of MND, provided identification of disease cases is sufficiently accurate. Follow-up in many such studies relies on linkage to routinely-collected health datasets. We systematically evaluated the accuracy of such datasets in identifying MND cases.MethodsWe performed an electronic search of MEDLINE, EMBASE, Cochrane Library and Web of Science for studies published between 01/01/1990-16/11/2015 that compared MND cases identified in routinely-collected, coded datasets to a reference standard. We recorded study characteristics and two key measures of diagnostic accuracy-positive predictive value (PPV) and sensitivity. We conducted descriptive analyses and quality assessments of included studies.ResultsThirteen eligible studies provided 13 estimates of PPV and five estimates of sensitivity. Twelve studies assessed hospital and/or death certificate-derived datasets; one evaluated a primary care dataset. All studies were from high income countries (UK, Europe, USA, Hong Kong). Study methods varied widely, but quality was generally good. PPV estimates ranged from 55-92% and sensitivities from 75-93%. The single (UK-based) study of primary care data reported a PPV of 85%.ConclusionsDiagnostic accuracy of routinely-collected health datasets is likely to be sufficient for identifying cases of MND in large-scale prospective epidemiological studies in high income country settings. Primary care datasets, particularly from countries with a widely-accessible national healthcare system, are potentially valuable data sources warranting further investigation.

ObjectiveWe performed a systematic review of the accuracy of patient self-report of stroke to inform approaches to ascertaining and confirming stroke cases in large prospective studies.MethodsWe sought studies comparing patient self-report against a reference standard for stroke. We extracted data on survey method(s), response rates, participant characteristics, the reference standard used, and the positive predictive value (PPV) of self-report. Where possible we also calculated sensitivity, specificity, negative predictive value (NPV), and stroke prevalence. Study-level risk of bias was assessed using the Quality Assessment of Diagnostic Studies tool (QUADAS-2).ResultsFrom >1500 identified articles, we included 17 studies. Most asked patients to report a lifetime history of stroke but a few limited recall time to ≤5 years. Some included questions for transient ischaemic attack (TIA) or stroke synonyms. No study was free of risk of bias in the QUADAS-2 assessment, the most frequent causes of bias being incomplete reference standard data, absence of blinding of adjudicators to self-report status, and participant response rates (75% in all but one study. It was not possible to assess the influence of recall time or of the question(s) asked on PPV or sensitivity.ConclusionsCharacteristics of the study population strongly influence self-report accuracy. In population-based studies with low stroke prevalence, a large proportion of self-reported strokes may be false positives. Self-report is therefore unlikely to be helpful for identifying cases without subsequent confirmation, but may be useful for case ascertainment in combination with other data sources.

Long-term follow-up of population-based prospective studies is often achieved through linkages to coded regional or national health care data. Our knowledge of the accuracy of such data is incomplete. To inform methods for identifying stroke cases in UK Biobank (a prospective study of 503,000 UK adults recruited in middle-age), we systematically evaluated the accuracy of these data for stroke and its main pathological types (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage), determining the optimum codes for case identification.We sought studies published from 1990-November 2013, which compared coded data from death certificates, hospital admissions or primary care with a reference standard for stroke or its pathological types. We extracted information on a range of study characteristics and assessed study quality with the Quality Assessment of Diagnostic Studies tool (QUADAS-2). To assess accuracy, we extracted data on positive predictive values (PPV) and-where available-on sensitivity, specificity, and negative predictive values (NPV).37 of 39 eligible studies assessed accuracy of International Classification of Diseases (ICD)-coded hospital or death certificate data. They varied widely in their settings, methods, reporting, quality, and in the choice and accuracy of codes. Although PPVs for stroke and its pathological types ranged from 6-97%, appropriately selected, stroke-specific codes (rather than broad cerebrovascular codes) consistently produced PPVs >70%, and in several studies >90%. The few studies with data on sensitivity, specificity and NPV showed higher sensitivity of hospital versus death certificate data for stroke, with specificity and NPV consistently >96%. Few studies assessed either primary care data or combinations of data sources.Particular stroke-specific codes can yield high PPVs (>90%) for stroke/stroke types. Inclusion of primary care data and combining data sources should improve accuracy in large epidemiological studies, but there is limited published information about these strategies.

Extracellular matrix 1 (ECM1) is over-expressed in multiple epithelial malignancies. However, knowledge regarding the expression of ECM1 in melanomas and the mechanisms of ECM1 regulation is limited. In this study, we found that ECM1 is over-expressed in several melanoma cell lines, when compared to primary melanocytes, and furthermore, that ECM1 expression paralleled that of TFAP2C levels in multiple cell lines. Knockdown of TFAP2C in the A375 cell line with siRNA led to a reduction in ECM1 expression, and upregulation of TFAP2C with adenoviral vectors in the WM793 cell line resulted in ECM1 upregulation. Utilizing 5' RACE to identify transcription start sites (TSS) and luciferase reporter assays in the ECM1-overexpressing A375 cell line, we identified the minimal promoter region of human ECM1 and demonstrate that an approximately 100bp fragment upstream of the TSS containing a TATA box and binding sites for AP1, SP1 and Ets is sufficient for promoter activity. Chromatin immunoprecipitation and direct sequencing (ChIP-seq) for TFAP2C in the A375 cell line identified an AP2 regulatory region in the promoter of the ECM1 gene. Gelshift assays further confirmed binding of TFAP2C to this site. ECM1 knockdown reduces melanoma cell attachment and is consistent with findings that ECM1 overexpression has been associated with a poor prognosis. Our investigations show an as yet unrecognized role for TFAP2C in melanoma via its regulation of ECM1.

Multiple genes involved in endocytosis and endosomal protein trafficking in Drosophila have been shown to function as neoplastic tumor suppressor genes (nTSGs), including Endosomal Sorting Complex Required for Transport-II (ESCRT-II) components vacuolar protein sorting 22 (vps22), vps25, and vps36. However, most studies of endocytic nTSGs have been done in mosaic tissues containing both mutant and non-mutant populations of cells, and interactions among mutant and non-mutant cells greatly influence the final phenotype. Thus, the true autonomous phenotype of tissues mutant for endocytic nTSGs remains unclear. Here, we show that tissues predominantly mutant for ESCRT-II components display characteristics of neoplastic transformation and then undergo apoptosis. These neoplastic tissues show upregulation of c-Jun N-terminal Kinase (JNK), Notch, and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling. Significantly, while inhibition of JNK signaling in mutant tissues partially inhibits proliferation, inhibition of JAK/STAT signaling rescues other aspects of the neoplastic phenotype. This is the first rigorous study of tissues predominantly mutant for endocytic nTSGs and provides clear evidence for cooperation among de-regulated signaling pathways leading to tumorigenesis.

In Drosophila imaginal epithelia, cells mutant for the endocytic neoplastic tumor suppressor gene vps25 stimulate nearby untransformed cells to express Drosophila Inhibitor-of-Apoptosis-Protein-1 (DIAP-1), conferring resistance to apoptosis non-cell autonomously. Here, we show that the non-cell autonomous induction of DIAP-1 is mediated by Yorkie, the conserved downstream effector of Hippo signaling. The non-cell autonomous induction of Yorkie is due to Notch signaling from vps25 mutant cells. Moreover, activated Notch in normal cells is sufficient to induce non-cell autonomous Yorkie activity in wing imaginal discs. Our data identify a novel mechanism by which Notch promotes cell survival non-cell autonomously and by which neoplastic tumor cells generate a supportive microenvironment for tumor growth.

BACKGROUND:Genetic studies in yeast have identified class E vps genes that form the ESCRT complexes required for protein sorting at the early endosome. In Drosophila, mutations of the ESCRT-II component vps25 cause endosomal defects leading to accumulation of Notch protein and increased Notch pathway activity. These endosomal and signaling defects are thought to account for several phenotypes. Depending on the developmental context, two different types of overgrowth can be detected. Tissue predominantly mutant for vps25 displays neoplastic tumor characteristics. In contrast, vps25 mutant clones in a wild-type background trigger hyperplastic overgrowth in a non-autonomous manner. In addition, vps25 mutant clones also promote apoptotic resistance in a non-autonomous manner. PRINCIPAL FINDINGS:Here, we genetically characterize the remaining ESCRT-II components vps22 and vps36. Like vps25, mutants of vps22 and vps36 display endosomal defects, accumulate Notch protein and--when the tissue is predominantly mutant--show neoplastic tumor characteristics. However, despite these common phenotypes, they have distinct non-autonomous phenotypes. While vps22 mutations cause strong non-autonomous overgrowth, they do not affect apoptotic resistance. In contrast, vps36 mutations increase apoptotic resistance, but have little effect on non-autonomous proliferation. Further characterization reveals that although all ESCRT-II mutants accumulate Notch protein, only vps22 and vps25 mutations trigger Notch activity. CONCLUSIONS/SIGNIFICANCE:The ESCRT-II components vps22, vps25 and vps36 display common and distinct genetic properties. Our data redefine the role of Notch for hyperplastic and neoplastic overgrowth in these mutants. While Notch is required for hyperplastic growth, it appears to be dispensable for neoplastic transformation.

Objective: We performed a systematic review of the accuracy of patient self-report of stroke to inform approaches to ascertaining and confirming stroke cases in large prospective studies. Methods: We sought studies comparing patient self-report against a reference standard for stroke. We extracted data on survey method(s), response rates, participant characteristics, the reference standard used, and the positive predictive value (PPV) of self-report. Where possible we also calculated sensitivity, specificity, negative predictive value (NPV), and stroke prevalence. Study-level risk of bias was assessed using the Quality Assessment of Diagnostic Studies tool (QUADAS-2). Results: From >1500 identified articles, we included 17 studies. Most asked patients to report a lifetime history of stroke but a few limited recall time to ≤5 years. Some included questions for transient ischaemic attack (TIA) or stroke synonyms. No study was free of risk of bias in the QUADAS-2 assessment, the most frequent causes of bias being incomplete reference standard data, absence of blinding of adjudicators to self-report status, and participant response rates (<80%). PPV of self-report ranged from 22–87% (17 studies), sensitivity from 36–98% (10 studies), specificity from 96–99.6% (10 studies), and NPV from 88.2–99.9% (10 studies). PPV increased with stroke prevalence as expected. Among six studies with available relevant data, if confirmed TIAs were considered to be true rather than false positive strokes, PPV of self-report was >75% in all but one study. It was not possible to assess the influence of recall time or of the question(s) asked on PPV or sensitivity. Conclusions: Characteristics of the study population strongly influence self-report accuracy. In population-based studies with low stroke prevalence, a large proportion of self-reported strokes may be false positives. Self-report is therefore unlikely to be helpful for identifying cases without subsequent confirmation, but may be useful for case ascertainment in combination with other data sources. [ABSTRACT FROM AUTHOR]

Multiple genes involved in endocytosis and endosomal protein trafficking in Drosophila have been shown to function as neoplastic tumor suppressor genes (nTSGs), including Endosomal Sorting Complex Required for Transport-II (ESCRT-II) components vacuolar protein sorting 22 (vps22), vps25, and vps36. However, most studies of endocytic nTSGs have been done in mosaic tissues containing both mutant and non-mutant populations of cells, and interactions among mutant and non-mutant cells greatly influence the final phenotype. Thus, the true autonomous phenotype of tissues mutant for endocytic nTSGs remains unclear. Here, we show that tissues predominantly mutant for ESCRT-II components display characteristics of neoplastic transformation and then undergo apoptosis. These neoplastic tissues show upregulation of c-Jun N-terminal Kinase (JNK), Notch, and Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling. Significantly, while inhibition of JNK signaling in mutant tissues partially inhibits proliferation, inhibition of JAK/STAT signaling rescues other aspects of the neoplastic phenotype. This is the first rigorous study of tissues predominantly mutant for endocytic nTSGs and provides clear evidence for cooperation among de-regulated signaling pathways leading to tumorigenesis. [ABSTRACT FROM AUTHOR]