Objective: Nonsurgical and surgical options are available for transgender vocal feminization. This systematic review explores the efficacy of feminizing voice therapy and phonosurgery. Methods: A systematic review was performed using PubMed, Cinahl Plus, Ovid SP, Web of Science, Science Direct, and Google Scholar with terms related to transgender phonosurgery and voice therapy. Included studies were outcomes-based vocal feminization interventions for transgender women. Data were collected on pre- and postintervention fundamental frequency (F0), externally measured vocal femininity, patient satisfaction, and complications. Results: Two hundred twelve studies were identified and 20 met inclusion criteria. Postintervention patient satisfaction was approximately 80% to 85% for voice therapy, endoscopic shortening, and cricothyroid approximation. Complications were reported for each phonosurgery technique, most commonly decreased mean phonation time and loudness. Of the 20 studies, 17 were used for meta-analysis of F0 change. F0 increased by 31 Hz with voice therapy alone, 26 Hz with laser reduction glottoplasty, 39 Hz with cricothyroid approximation, and 72 Hz with endoscopic shortening. Conclusion: The literature supports both voice therapy and phonosurgery, depending on a patient's magnitude of desired pitch change and tolerance for cost and potential complications. Most will likely benefit from voice therapy, as it is highly satisfactory, raises vocal pitch, and is noninvasive. However, endoscopic shortening is also highly satisfactory and provides the greatest absolute increase in vocal pitch. If surgery is chosen, postoperative voice therapy may additionally increase F0, stabilize the voice, and create a more female timbre. However, further studies will be necessary to provide definitive clinical recommendations.
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors.
Nearly one-third of patients with calcium stones have hyperuricosuria. In vitro studies and clinical trials have investigated the relationship between uric acid and calcium stones, but the association between hyperuricosuria and calcium stone formation in patients is still being debated. Uric acid appears to cause salting out of calcium oxalate in human urine. However, the importance of this in vitro phenomenon to the proposed association is not supported in cross-sectional observational studies. A small placebo-controlled randomized clinical trial showed that allopurinol decreased the rate of recurrent calcium oxalate calculi in patients with hyperuricosuria and normocalciuria. An assessment of the effect of combination therapy of allopurinol with indapamide showed no additive effect. Allopurinol may have antioxidant effects that are responsible for its reducing calcium stone formation, which are independent of xanthine oxidase inhibition. In addition, a newer xanthine oxidoreductase inhibitor, febuxostat, may also be effective in the prevention of calcium stones, as it reduces urinary uric acid excretion.
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