Interdisciplinary Considerations for Nasolabial Repair During a Global Pandemic.

BACKGROUND: At the declaration of the global pandemic on March 11, 2020, many hospitals and institutions developed a tiered framework for the stratification and prioritization of elective surgery. Cleft lip and palate repair was classified as low acuity, and nasoalveolar molding (NAM) clinics were closed. Anticipating the consequences of delayed cleft care and the additional burden this would cause families, we reassessed our risk-stratification and perioperative algorithms. We hypothesized we could safely optimize nasolabial repair without burdening our care systems and without increasing COVID-19-related morbidity/mortality. METHODS: Our multidisciplinary cleft team reevaluated patient selection to maximize surgical impact. Perioperative protocols were adjusted, and COVID-19 preoperative testing was utilized before nasolabial repair and prior to suture removal under anesthesia. RESULTS: Early in the pandemic, unilateral cleft repair was prioritized and successfully completed on 9 patients. There were no complications related to COVID-19. Nasoalveolar molding clinic was reopened after total patient volume was significantly decreased. CONCLUSIONS: We offer an approach for surgical management of nasolabial clefts during a global pandemic. Although guidelines have suggested postponing all cleft care, we found that at our dedicated pediatric hospital with low burden of COVID-19 and adequate resources, we could follow a strategy to safely resume cleft care while decreasing burden on our patients' families and care delivery systems.

The Role of Voice Therapy and Phonosurgery in Transgender Vocal Feminization.

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.

The nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant response promotes melanocyte viability and reduces toxicity of the vitiligo-inducing phenol monobenzone.

Vitiligo, characterised by progressive melanocyte death, can be initiated by exposure to vitiligo-inducing phenols (VIPs). VIPs generate oxidative stress in melanocytes and activate the master antioxidant regulator NRF2. While NRF2-regulated antioxidants are reported to protect melanocytes from oxidative stress, the role of NRF2 in the melanocyte response to monobenzone, a clinically relevant VIP, has not been characterised. We hypothesised that activation of NRF2 may protect melanocytes from monobenzone-induced toxicity. We observed that knockdown of NRF2 or NRF2-regulated antioxidants NQO1 and PRDX6 reduced melanocyte viability, but not viability of keratinocytes and fibroblasts, suggesting that melanocytes were preferentially dependent upon NRF2 activity for growth compared to other cutaneous cells. Furthermore, melanocytes activated the NRF2 response following monobenzone exposure and constitutive NRF2 activation reduced monobenzone toxicity, supporting NRF2's role in the melanocyte stress response. In contrast, melanocytes from individuals with vitiligo (vitiligo melanocytes) did not activate the NRF2 response as efficiently. Dimethyl fumarate-mediated NRF2 activation protected normal and vitiligo melanocytes against monobenzone-induced toxicity. Given the contribution of oxidant-antioxidant imbalance in vitiligo, modulation of this pathway may be of therapeutic interest.

Arrhythmia Resolution After Successful Parathyroidectomy for Primary Hyperparathyroidism.

The prevalence of primary hyperparathyroidism (PHPT) is increasing as routine laboratory testing for calcium and parathyroid hormone becomes more prevalent due to heightened awareness of the disease. PHPT affects multiple organ systems including the cardiovascular system. This case report highlights a patient with first degree atrio-ventricular block pre-operatively that resolved after resection of her parathyroid adenoma. This case emphasizes the importance of treating asymptomatic hyperparathyroidism to optimize cardiac function.

Perioperative Pain Management in Cleft Lip and Palate Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

BACKGROUND: Developing effective strategies to manage perioperative pain remains a focus of cleft care. The present study's purpose was to systematically review perioperative pain control strategies for cleft lip and palate repair. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed. Primary outcomes included pain scale scores and time to analgesia failure. Cohen d normalized effect size permitted comparison between studies, and a fixed-effects model was used for analysis. I2 and Q-statistic p values were calculated. RESULTS: Twenty-three studies were included: eight of 23 studies provided data for meta-analytic comparison. Meta-analyses evaluated the efficacy of intraoperative nerve blocks on postoperative pain management. Meta-analysis included a total of 475 treatment and control patients. Cleft lip studies demonstrated significantly improved pain control with a nerve block versus placebo by means of pain scale scores ( p < 0.001) and time to analgesia failure ( p < 0.001). Measurement of effect size over time demonstrated statistically significant pain relief with local anesthetic. Palatoplasty studies showed significantly improved time to analgesia failure ( p < 0.005) with maxillary and palatal nerve blocks. Multiple studies demonstrated an opioid-sparing effect with the use of local anesthetics and other nonopioid medications. Techniques for nerve blocks in cleft lip and palate surgery are reviewed. CONCLUSIONS: The present systematic review and meta-analysis of randomized controlled studies demonstrates that intraoperative nerve blocks for cleft lip and palate surgery provide effective pain control. Opioid-sparing effects were appreciated in multiple studies. Intraoperative nerve blocks should be considered in all cases of cleft lip and palate repair to improve postoperative pain management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.

Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but FLT3 targeted therapy has produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multitargeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting.

Sacral and Ischial Pressure Ulcer Management With Negative-Pressure Wound Therapy With Instillation and Dwell.

BACKGROUND: The addition of topical fluid instillation, a programmable "dwell" time and a novel foam-wound interface to the established wound healing benefits of negative-pressure wound therapy (NPWT) works synergistically to benefit patients with complex wounds. This engineering breakthrough for wound care has been termed NPWT with instillation and dwell (NPWTi-d), and the new foam dressings are reticulated open cell foam dressings specifically designed for use with NPWTi-d. This combined technology has shown promise in chronic, complex wounds and has potential for the management of sacral and ischial pressure wounds. METHODS: A qualitative comprehensive review was performed analyzing articles from PubMed and Medline that reported on the use of NPWTi-d in sacral or ischial pressure ulcers. Case series and case reports were predominant, and results of cases specific to sacral and ischial pressure wounds were extracted from larger studies and summarized for presentation. RESULTS: Compared with conventional NPWT alone, NPWTi-d has been shown to help irrigate the wound, remove fibrinous debris, and promote granulation tissue formation. This is associated with a decreased number of operative debridements and decreased hospital length of stay. CONCLUSIONS: This technology is rapidly demonstrating expanded utilization in hospitalized patients with chronic sacral and ischial pressure ulcers. When used correctly, NPWTi-d serves as an effective "bridge to defined endpoint": whether that is a flap reconstruction, skin grafting, or discharge home with a stable chronic wound and simplified wound care.

Treatment of calcium nephrolithiasis in the patient with hyperuricosuria.

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.

Metabolic evaluation of first-time and recurrent stone formers.

Evaluation of stone formers should include careful attention to medications, past medical history, social history, family history, dietary evaluation, occupation, and laboratory evaluation. Laboratory evaluation requires at least serum chemistries and urinalysis. Twenty-four-hour urine collections are most appropriate for patients with recurrent stones or complex medical histories. However, these collections may be appropriate for some first-time stone formers, including those with comorbidities or large stones. Although twin studies demonstrate that heritability accounts for at least 50% of the kidney stone phenotype, the responsible genes are not clearly identified, and so genetic testing is rarely indicated.

A potential therapeutic target for FLT3-ITD AML: PIM1 kinase.

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.