Zoledronate in the prevention of Paget's (ZiPP) : protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

Introduction Paget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. Methods and analysis People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events

Oldest skeleton of a fossil flying squirrel casts new light on the phylogeny of the group

Flying squirrels are the only group of gliding mammals with a remarkable diversity and wide geographical range. However, their evolutionary story is not well known. Thus far, identification of extinct flying squirrels has been exclusively based on dental features, which, contrary to certain postcranial characters, are not unique to them. Therefore, fossils attributed to this clade may indeed belong to other squirrel groups. Here we report the oldest fossil skeleton of a flying squirrel (11.6 Ma) that displays the gliding-related diagnostic features shared by extant forms and allows for a recalibration of the divergence time between tree and flying squirrels. Our phylogenetic analyses combining morphological and molecular data generally support older dates than previous molecular estimates (\~23 Ma), being congruent with the inclusion of some of the earliest fossils (\~36 Ma) into this clade. They also show that flying squirrels experienced little morphological change for almost 12 million years