Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.     

A literature-based treatment algorithm for low-grade neuroendocrine liver metastases

BackgroundThe optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM.MethodsA treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments.ResultsApplying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics.ConclusionThis literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.     

A systematic review of injuries in gymnastics

Objectives: To identify all studies of gymnastics injuries and assess injury rates, types, locations, and causes.

Methods: Seven electronic and two grey literature databases were searched. Two reviewers independently assessed titles/abstracts, abstracted data, and calculated average rates weighted by study size.

Results: One study (n = 963) of three Olympic games (2008,2012,2016) provided injury rates for females of 86.4/1000gymnasts and males 79.9. For 29 databases one study of males (n = 64) provided a rate of 8.8 injuries/1000hours/AE (AE = athletic-exposure) and three of females varied rates (8.5, 9.4, and 91). Three studies for males (n = 153) provided a weighted average rate of 1.4 injuries/1000hours/training, and for females six studies (n = 476) 1.5 injuries. Four studies of males (n = 286) provided a weighted average of 678 injuries/1000gymnasts per year and eight studies of females (n = 1,764) a rate of 306. Of 19 surveys, eight provided rates for females (n = 1,463) of 596 injuries/gymnast per year and two for males (n = 40) a rate of 1,036. In the Olympics injuries were preponderately lower limb (63%) then trunk (23%) and upper limb (14%); injury type was sprains (35%) followed by tendinopathy/arthritis/impingements (17%), contusions (10%), and fractures (7%). Five database studies provided injury location data for 274 males: averages weighted by study size were upper extremity 42.8%, lower extremity 33.6%, torso/spine 11.8%, and head/neck 4.9% and 12 studies with 843 females provided average rates for lower extremity 51%, upper extremity 30.8%, torso/spine 13% and head/neck 0.8%. Official gymnastics organizations’ websites provide no readily available data about injury rates or methods of prevention.

Conclusions: Studies need to collect comprehensive data for injury rates by training/competitions, gender, age, injury location/type/cause. Studies could assess whether trainers and physiotherapists monitoring gymnasts closely for injury risk would reduce injuries. Studies including randomized controlled trials (RCTs) of interventions in training, videotaping and performance feedback to reduce injury rates would be helpful.