Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. Receptor activator for NF-κB ligand (RANKL or TNFSF11), a tumor necrosis factor (TNF) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptors, DNAX-associated protein 12 kDa size (DAP12) and FcεRI gamma chain (FcRγ). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain and, therefore, must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including triggering receptor expressed on myeloid cells 2 (TREM2), myeloid DAP12-associated lectin (MDL-1), and sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15); while FcRγ pairs with a different set of receptors including osteoclast-specific activating receptor (OSCAR), paired immunoglobulin receptor A (PIR-A), and Fc receptors. The ligands for many of these receptors in the bone microenvironment remain unknown. Here, we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis. Co-stimulation and the effects of ITAM-signaling have turned out to be complex, and now include paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.

BACKGROUND

Effective communication between referring and specialty providers is key to optimizing patient safety. Communication was assessed in an electronic referral system by review of referrals to a public urban health care system's gastroenterology clinic that were not scheduled for appointments.

METHODS

All electronic referrals to a publicly funded, urban health care system's adult gastroenterology clinic from November 1, 2009, to November 30, 2010, were reviewed that did not result in scheduling of appointments. An assessment was made of whether in-person visits were unnecessary by preconsultation exchange or whether the referrals remained unscheduled for other reasons. For the latter group, reasons why the referrals remained unscheduled were examined, and medical records were reviewed for actual patient harm when sufficient information was present in the chart or for potential harm when no further information about the referral complaint was available.

RESULTS

Eighty-six (32%) of 266 not-scheduled referrals were resolved via preconsultation exchange. For another 96 (36%), patients were not ultimately considered to require appointments or were scheduled via other routes. Nine patients received unplanned care while awaiting scheduling decisions, 5 of whom had harm that was related to referral complaints, although scheduling of appointments may not have avoided this harm. Of 75 patients for whom further information was not available about the referral complaints, most were not seen back in primary care, and 55 (73%) had potential for major harm.

CONCLUSION

Few adverse outcomes in electronic referrals not scheduled for in-person gastroenterology visits were found, and none were clearly due to communication lapses in the referral process. Contributors to the potential for harm in referrals that were unintentionally left unscheduled included discontinuity of care and lack of patient or provider follow-up.

Recent studies have focused on associations of the APOL1 risk variants with outcomes beyond kidney disease, including cardiovascular disease and mortality. Ma and colleagues now expand on this growing but contradicting body of work. Their analysis of a prevalent cohort of African American hemodialysis patients shows that the risk variants are associated with a survival benefit among nondiabetics. Whether this simply reflects a healthier status at hemodialysis initiation among those carrying 2 risk variants or whether these variants truly confer a survival advantage is unclear.