A clinical research integration special program (CRISP) for young women with primary ovarian insufficiency.

Large-scale medical sequencing provides a focal point around which to reorganize health care and health care research. Mobile health (mHealth) is also currently undergoing explosive growth and could be another innovation that will change the face of future health care. We are employing primary ovarian insufficiency (POI) as a model rare condition to explore the intersection of these potentials. As both sequencing capabilities and our ability to intepret this information improve, sequencing for medical purposes will play an increasing role in health care beyond basic research: it will help guide the delivery of care to patients. POI is a serious chronic disorder and syndrome characterized by hypergonadotrophic hypogonadism before the age of 40 years and most commonly presents with amenorrhea. It may have adverse health effects that become fully evident years after the initial diagnosis. The condition is most commonly viewed as one of infertility, however, it may also be associated with adverse long-term outcomes related to inadequate bone mineral density, increased risk of cardiovascular disease, adrenal insufficiency, hypothyroidism and, if pregnancy ensues, having a child with Fragile X Syndrome. There may also be adverse outcomes related to increased rates of anxiety and depression. POI is also a rare disease, and accordingly, presents special challenges. Too often advances in research are not effectively integrated into community care at the point of service for those with rare diseases. There is a need to connect community health providers in real time with investigators who have the requisite knowledge and expertise to help manage the rare disease and to conduct ongoing research. Here we review the pathophysiology and management of POI and propose the development of an international Clinical Research Integration Special Program (CRISP) for the condition.

Synthesis of Iridium(III) Carboxamides via the Bimetallic Reaction between Cp(PMe(3))IrPh(OH) and [Cp(PMe(3))Ir(Ph)NCR](+).

Reaction of Cp(PMe(3))IrPh(OH) (1) with nitriles is undetectably slow in benzene solution at room temperature. However, in the presence of Cp(PMe(3))IrPh(OTf) (2) (OTf = O(3)SCF(3)), the reaction is strongly catalyzed, leading to iridium(III) carboxamides Cp(PMe(3))IrPh[NHC(O)R] (6a-d) [R = C(6)H(4)CH(3) (6a), C(6)H(5) (6b), C(6)H(4)CF(3) (6c), CH(3) (6d)]. We propose that these transformations occur by initial displacement of the trifluoromethanesulfonate ("triflate") anion of 2 by a molecule of nitrile, leading to a nitrile-substituted iridium cation, [Cp(PMe(3))IrPh(NCR)](+) (10). Following this, the nucleophilic hydroxide group of 1 attacks the (activated) nitrile molecule bound in 10, leading (after proton transfer) to the iridium carboxamide complex. In the case of nitriles possessing hydrogens alpha to the cyano group, competitive loss of one of these protons is observed, leading to iridium C-bound cyanoenolates such as Cp(PMe(3))(Ph)Ir(CH(2)CN) (7). Protonolysis of carboxamides 6a-d with HCl yields Cp(PMe(3))IrPh(Cl) (9) and the free amides. A pronounced solvent effect is observed when the reaction between 1 and nitriles catalyzed by 2 is carried out in THF solution. The basic hydroxide ligand of 1 induces an overall dehydration/cyclization reaction of the coordinated aromatic nitrile. For example, the reaction of 1 with p-trifluorotolunitrile and a catalytic amount of 2 leads to the formation of 6c, water, [Ph(PMe(3))Ir[C(5)Me(4)CH(2)C(C(6)H(4)CF(3))N]] (12), and [Ph(PMe(3))Ir(C(5)Me(4)CH(2)C(C(6)H(4)CF(3))NH)]OTf (13). A mechanism to explain the formation of both 12 and 13 and the role each compound plays in the formation of the iridium carboxamides is proposed.