Debate: Gold standard or go for gold? The pros and cons of waiting for gold standard evidence of effectiveness for adolescent depression and self-harm interventions versus acting with the precautionary principle in current political times

There is increasing concern about the prevalence of depression and self-harm among children adolescents in many countries. Governments who commission and fund psychological interventions to address these difficulties want to know what is effective. The techniques available for synthesising gold standard evidence are increasingly sophisticated, but there are many criticisms of being completely reliant on this approach. A precautionary approach, where public policy decision-makers acknowledge that where the evidence is limited, the benefits of certain interventions are thought to outweigh the risks, including the risk of doing nothing. This later element may be particularly important in the domain of depression and self-harm, as both are associated with elevated risk of death by suicide.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Diagnostic Specificity of Neurophysiological Endophenotypes in Schizophrenia and Bipolar Disorder

Background: The utility of an endophenotype depends on its ability to reduce complex disorders into stable, genetically linked phenotypes. P50 and P300 event-related potential (ERP) measures are endophenotype candidates for schizophrenia; however, their abnormalities are broadly observed across neuropsychiatric disorders. This study examined the diagnostic efficiency of P50 and P300 in schizophrenia as compared with healthy and bipolar disorder samples. Supplemental ERP measures and a multivariate classification approach were evaluated as methods to improve specificity. Methods: Diagnostic classification was first modeled in schizophrenia (SZ = 50) and healthy normal (HN = 50) samples using hierarchical logistic regression with predictors blocked by 4 levels of analysis: (1) P50 suppression, P300 amplitude, and P300 latency; (2) N100 amplitude; (3) evoked spectral power; and (4) P50 and P300 hemispheric asymmetry. The optimal model was cross-validated in a holdout sample (SZ = 34, HN = 31) and tested against a bipolar (BP = 50) sample. Results: P50 and P300 endophenotypes classified SZ from HN with 71% accuracy (sensitivity = .70, specificity = .72) but did not differentiate SZ from BP above chance level. N100 and spectral power measures improved classification accuracy of SZ vs HN to 79% (sensitivity = .78, specificity = .80) and SZ vs BP to 72% (sensitivity = .74, specificity = .70). Cross validation analyses supported the stability of these models. Conclusions: Although traditional P50 and P300 measures failed to differentiate schizophrenia from bipolar participants, N100 and evoked spectral power measures added unique variance to classification models and improved accuracy to nearly the same level achieved in comparison of schizophrenia to healthy individuals.Key words: event-related potential, P50, P300, N100, gamma frequency     

Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.