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It is difficult to interpret Toppan’s general insanity diagnosis through the lens of modern psychology, but it seems that mental health experts of the time believed Jane had lost touch with reality. One physician said that Jane also grew increasingly suspicious over time. An expert who examined Toppan told The Boston Post that hers was “one of the strangest cases of diseased mind he had ever seen.” 57 While not diagnosing her, Toppan’s symptoms may be indicative of schizophrenia, although the term and diagnosis were not introduced until after her assessment. She had reportedly lost touch with reality; expressed bizarre behavior (including kissing a dying patient experiencing a death rattle); 58 had an inappropriate affect (she liked autopsies and said that being in jail was the happiest she had ever been); 59 suffered from memory impairment (she told her lawyer that, at times, she had “great difficulty” remembering what she had done); 60 and experienced delusions of grandeur. Further, schizophrenia has a substantial genetic basis and is thus seen in siblings, 61 and Toppan’s sister (unnamed) was also committed to an insane asylum. 62 Nevertheless, Toppan is no longer around to interview and assess. Clark, D. E. et al. The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. Cancer Res. 65, 3108–3116 (2005). McClung, M.R. Romosozumab for the treatment of osteoporosis. Osteoporos. Sarcopenia 2018, 4, 11–15. [ Google Scholar] [ CrossRef]

The age at which a FSK commits her first murder might be a key variable in the commission of these crimes. While our dataset included this information for most cases, we must remember that it is possible that some of a killer’s crimes, including her first crime, may be unknown to police. Nevertheless, we determined that the mean age of a FSK’s first act was 32, with a statistical standard deviation (SD) of 11.7 years. 36 The ages themselves demonstrated considerable variation, with FSKs ranging from 16 to 65 at the time of their first documented murder. However, about three-quarters of the FSKs in our sample were in their 20s or 30s when they first killed. Iqbal, J.; Sun, L.; Zaidi, M. Denosumab for the treatment of osteoporosis. Curr. Osteoporos. Rep. 2010, 8, 163–167. [ Google Scholar] [ CrossRef] Maricic, M. The role of zoledronic acid in the management of osteoporosis. Clin. Rheumatol. 2010, 29, 1079–1084. [ Google Scholar] [ CrossRef] The primary obstacles to obtaining results are 1. user acceptance/adoption and 2. accountability. We have experienced much higher adoption when digital solutions are paired with in-person provider treatments and follow-ups. There have been similar results for less serious MSKs with telehealth provider Chiu, Y.G.; Ritchlin, C.T. Denosumab: Targeting the RANKL pathway to treat rheumatoid arthritis. Expert. Opin. Biol. Ther. 2017, 17, 119–128. [ Google Scholar] [ CrossRef][ Green Version]

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Berns, K. et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428, 431–437 (2004). Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nature Cell Biol. 4, 556–564 (2002).

Wang, C. Efficacy and Safety of Zoledronic Acid for Treatment of Postmenopausal Osteoporosis: A Meta-Analysis of Randomized Controlled Trials. Am. J. Ther. 2017, 24, e544–e552. [ Google Scholar] [ CrossRef] [ PubMed] Braun, A.C.; Gutmann, M.; Ebert, R.; Jakob, F.; Gieseler, H.; Lühmann, T.; Meinel, L. Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors. Pharm. Res. 2017, 34, 58–72. [ Google Scholar] [ CrossRef] Dummler, B. A. et al. Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. J. Biol. Chem. 280, 13304–13314 (2005).Newman, M.R.; Benoit, D.S. Local and targeted drug delivery for bone regeneration. Curr. Opin. Biotechnol. 2016, 40, 125–132. [ Google Scholar] [ CrossRef][ Green Version] consultations. Ultimately, there is a definite place for digital MSK solutions in the future landscape of MSK care and these will inevitably continue to improve as more employers start to realize the cost savings of these programs and the improved health and productivity of their employees that utilize them. A digital MSK solution is a valuable complement to a comprehensive MSK wellness program that also includes telehealth and in-person care. Mora, A., Komander, D., van Aalten, D. M. & Alessi, D. R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161–170 (2004).

Zeniou, M., Ding, T., Trivier, E. & Hanauer, A. Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin–Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum. Mol. Gen. 11, 2929–2940 (2002).

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Newton, A. C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370, 361–371 (2003).

Snedeker, J.G.; Foolen, J. Tendon injury and repair—A perspective on the basic mechanisms of tendon disease and future clinical therapy. Acta Biomater. 2017, 63, 18–36. [ Google Scholar] [ CrossRef] [ PubMed] A functional unit of protein synthesis that consists of several ribosomes attached along the length of a single molecule of mRNA. XEXD caspase-inhibitory boxTrivier, E. et al. Mutations in the kinase Rsk-2 associated with Coffin–Lowry syndrome. Nature 384, 567–570 (1996). Provides the first direct evidence that abnormalities in the MAPK–RSK signalling pathway cause Coffin–Lowry syndrome. Newman, M.R.; Russell, S.G.; Schmitt, C.S.; Marozas, I.A.; Sheu, T.-J.; Puzas, J.E.; Benoit, D.S.W. Multivalent Presentation of Peptide Targeting Groups Alters Polymer Biodistribution to Target Tissues. Biomacromolecules 2018, 19, 71–84. [ Google Scholar] [ CrossRef] Coskun Benlidayi, I. Denosumab in the treatment of glucocorticoid-induced osteoporosis. Rheumatol. Int. 2018, 38, 1975–1984. [ Google Scholar] [ CrossRef] [ PubMed] Evans, S.F.; Parent, J.B.; Lasko, C.E.; Zhen, X.; Knothe, U.R.; Lemaire, T.; Knothe Tate, M.L. Periosteum, bone’s “smart” bounding membrane, exhibits direction-dependent permeability. J. Bone Miner. Res. 2013, 28, 608–617. [ Google Scholar] [ CrossRef]