Pinch Grafting: A Systematic Review of Modern Perspectives and Applications in Dermatologic Surgery and Wound Healing.

BACKGROUND: Pinch grafting has experienced a resurgence in interest in recent years, stemming from its simplicity, safety, and potential in restoring tissue integrity. While historically employed for chronic nonhealing wounds, pinch grafts have shown promise following surgical procedures, particularly those involving the lower extremities. OBJECTIVE: To systematically review the literature and present an updated overview of the current applications of pinch grafting. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In collaboration with a medical reference librarian, the PubMed, Embase, Scopus, and Web of Science databases were searched for studies reporting on the use of pinch grafting from 2000 onward. The references of each included article were also screened. RESULTS: Ten articles met final inclusion criteria. In total, 300 patients underwent pinch grafting for treatment of skin ulceration, while an additional 35 cases were performed as an alternative to primary closure following skin cancer resection. Overall, pinch grafting was safe and well tolerated, with minimal adverse outcomes reported. CONCLUSION: Pinch grafting is a safe, straightforward, and effective technique to promote the healing of chronic wounds. While the procedure shows early promise in emerging applications within dermatologic surgery, only about 10% of the reported cases involved this indication, reflecting a need for further research in this area.

Hidradenocarcinoma: A Case Series From the Scripps Clinic With a Systematic Review of the Literature.

BACKGROUND: Hidradenocarcinoma (HAC) is a rare adnexal carcinoma. To the best of the authors' knowledge, there are no published systematic reviews on HAC. OBJECTIVE: To incorporate a case series from the authors' institution and systematically integrate reported information to provide a reference tool for optimization of diagnosis and management. METHODS: A comprehensive MEDLINE search was conducted from database inception to 2021 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This yielded 225 studies with 165 cases of HAC. References of included articles were also searched. In addition, 9 patients with HAC were identified from the authors' institution over the past 10 years. RESULTS: The mean age of HAC presentation is 60 years with a slight male predilection (60%). The head and neck is the most commonly affected region. Over 36% of cases either presented with metastatic disease or went on to metastasize. The most common treatment type was wide local excision, followed by Mohs micrographic surgery. CONCLUSION: Early detection with accurate histologic interpretation is prudent in all cases of HAC. Wide local excision is the current first-line treatment. However, Mohs micrographic surgery offers complete marginal analysis with evidence of reduced risk of metastasis and better outcomes compared with wide local excision. Currently, there are no National Comprehensive Cancer Network guidelines for the treatment of HAC, and consensus guidelines are limited to tumor and nodal metastasis staging provided by the American Joint Committee on Cancer, eighth edition. Thus, this case series and systematic review integrates important aspects of diagnosis, workup, and management of HAC.

Liposomal and Nonliposomal Bupivacaine for Mohs Surgery: A Systematic Review.

BACKGROUND: Lidocaine is the most commonly used local anesthetic for Mohs micrographic surgery (MMS), but given its limited half-life, postoperative pain remains a significant concern for patients. Bupivacaine is used in various surgical subspecialty procedures and has demonstrated improved pain control compared with lidocaine. However, its role in MMS is insufficiently explored. OBJECTIVE: To systematically review the current literature for reports on use of bupivacaine, traditional nonliposomal and newer liposomal formulations, for MMS. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. The MEDLINE, PubMed, and EMBASE databases were queried for articles presenting original data on the use of bupivacaine for MMS. RESULTS: Of 483 potentially relevant articles, 3 studies met final inclusion criteria, capturing a total of 253 patients involved in primary investigations comparing bupivacaine to traditional local anesthesia for MMS. Bupivacaine was well-tolerated and associated with comparable or modestly reduced intraoperative and postoperative pain and opioid use. CONCLUSION: Bupivacaine may have a role in prolonging intraoperative anesthesia, reducing acute postoperative pain, and reducing postoperative opioid use after MMS. However, large, prospective studies are needed to solidify the generalizability and clinical utility of these findings.

Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.

Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study.

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia.

BACKGROUND AND OBJECTIVE: Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5-14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5-18 years randomized to receive daily subcutaneous injections for 52 weeks). METHODS: Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. RESULTS: The exposure-response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 µg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 µg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 µg/kg to patients with achondroplasia aged 5-18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. CONCLUSIONS: The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. CLINICAL TRIALS REGISTRATION: NCT02055157, NCT03197766, and NCT01603095.

Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia.

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery.

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40.

Effects of Premedication With Midazolam on Recovery and Discharge Times After Tonsillectomy and Adenoidectomy.

Background Midazolam is commonly used preoperatively for anxiety. Adverse effects data in pediatric patients with obstructive sleep apnea (OSA) undergoing tonsillectomy and adenoidectomy (T&A) is limited. Aims We hypothesized that preoperative midazolam increases the time to emergence from anesthesia and postoperative discharge. Secondary objectives assessed if patients receiving midazolam experienced increased side effects or complications from treatment. Methods This study was a retrospective chart review of patients undergoing T&A from July 2014 to December 2015. Midazolam receiving patients (midazolam group: MG) were compared to patients who did not (non-midazolam group: NMG). Multivariable analyses were performed and adjusted for predefined potential cofounder variables. Results Emergence and discharge times were 5.2 minutes (95% CI [-7.1, 17.4]; p=0.41) and 10.1 minutes (95% CI [-6.7, 26.8]; p=0.24) longer in MG. These results were not statistically significant. Comparing by OSA status, there was no statistical difference in emergence and discharge times between mild, moderate and severe OSA groups or between MG and NMG within each OSA group. Emergence and discharge times in moderate OSA was 6.1 minutes (95% CI [-17.6, 29.8]; p=0.61) and 18.8 minutes (95% CI [-16.4, 53.9]; p=0.29) longer than mild OSA, and in the severe OSA group, 2.6 minutes (95% CI [-19.9, 25.1]; p=0.82) shorter and 2.8 minutes (95% CI [-30.3, 35.9]; p=0.87) longer. The incidence of postoperative complications was comparable between MG and NMG groups. Conclusions Premedication with midazolam was not associated with prolonged emergence or discharge time or higher incidence of complications after anesthesia for T&A in patients with OSA.

Review of the Current State of Urine Drug Testing in Chronic Pain: Still Effective as a Clinical Tool and Curbing Abuse, or an Arcane Test?

PURPOSE OF REVIEW: Therapeutic use, misuse, abuse, and diversion of controlled substances in managing chronic non-cancer pain remain a major concern for physicians, the government, payers, and patients. The challenge remains finding effective diagnostic tools that can be clinically validated to eliminate or substantially reduce the abuse of controlled prescription drugs, while still assuring the proper treatment of those patients in pain. Urine drug testing still remains an important means of adherence monitoring, but questions arise as to its relevance and effectiveness. This review examines the role of UDT, determines its utility in current clinical practice, and investigates its relevance in current chronic pain management. RECENT FINDINGS: A review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Literature was searched from year 2000 to present examining the relevance and role of UDT in monitoring chronic opioid therapy along with reliability and accuracy, appropriate use, overuse, misuse, and abuse. There are only a limited number of reviews and investigations on UDT, despite the fact that clinicians who prescribe controlled medications for chronic states commonly are expected to utilize UDT. Therefore, despite highly prevalent use, there is a limited publication base from which to draw in this present study. Regardless of experience or training background, physicians and healthcare providers can much more adequately assess opioid therapy with the aid of UDT, which often requires confirmatory testing by a laboratory for clinical and therapeutic prescribing decisions. It has become a strongly recommended aspect of pain care with controlled substances locally, regionally, and nationally. Incorporating UDT for all patients in whom chronic opioid therapy is undertaken is consistent with state and national guidelines and best practice strategies. Practice standards vary as to the frequency of UDT locally, regionally, and nationally, however.

Management of Cutaneous Calciphylaxis.

Calciphylaxis is a deadly, painful disease with a 1-year mortality of up to 50%. The disease is commonly associated with patients with end-stage kidney disease (ESKD), but it can manifest in non-uremic patients as well. In patients who are undergoing dialysis, the incidence of calciphylaxis can range from 0.04% to 4%. The progressive arterial calcification seen in calciphylaxis can affect multiple body organs, including the skin, brain, lungs, and muscle. In cutaneous calciphylaxis, painful and non-healing nodules, plaques, and ulcers may appear, increasing morbidity for patients. Diagnosis can be difficult, and the condition can clinically appear similar to other dermatological diseases, especially in non-uremic patients. Currently, skin biopsy with histological analysis is the most reliable method to help diagnose the condition. In certain cases, the use of medical imaging may be helpful. Treatment of pain in this condition can be difficult and should be multimodal and include wound care as well as modification of risk factors. Analgesic options include opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), as well as analgesic options that are targeted for specific patients. There are currently multiple clinical trials underway that are studying targeted therapies for this condition.

Folic Acid Supplementation in Patients with Elevated Homocysteine Levels.

INTRODUCTION: Folic acid is the most important dietary determinant of homocysteine (Hcy). Hcy serves as a critical intermediate in methylation reactions. It is created from methionine and either converted back to methionine or transformed into cysteine. This process is aided through several enzymes and three vitamins, folic acid, B12, and B6. Daily supplementation with 0.5-5.0 mg of folic acid typically lowers plasma Hcy levels by approximately 25%. Hyperhomocysteinemia is a known risk factor for coronary artery disease. In this regard, elevated levels of Hcy have been found in a majority of patients with vascular disease. METHODS: A literature review of folic acid supplementation for various disease states including cardiovascular disease was conducted. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. RESULTS: In this review, we discuss the biochemistry of folic acid, Hcy biosynthesis, Hcy and hydrogen sulfide bioavailability, pathogenesis of hyperhomocysteinemia and its role as a risk factor for disease, and treatment studies with folic acid supplementation in disease states. CONCLUSION: Folic acid supplementation should be recommended to any patient who has an elevated Hcy level, and this level should be measured and treated at an early age, since folic acid is easily obtained and may likely reduce vascular disease and other deleterious pathologic processes in high-risk populations.

Novel Translocation in Acute Myeloid Leukemia: Case Report and Review of Risk-Stratification and Induction Chemotherapy in Patients With Acute Myeloid Leukemia.

Identification of chromosomal abnormalities in patients with acute myeloid leukemia (AML) has contributed substantially to our current understanding of the molecular pathogenesis underlying leukemogenesis, and risk-stratification based on molecular abnormalities both influences treatment strategies and aids in determining prognosis. While over 300 established mutations have been documented in AML, the enhanced availability of genetic analysis and the increase in awareness of uncommon chromosomal translocations have made it possible for rare, apparently unique translocations to become recognized and to ultimately gain prognostic significance. Hence, we present a case of AML with a novel, balanced 2;12 translocation involving breakpoints previously undescribed. Although the patient required second induction, first remission was ultimately achieved. While the prognostic significance of this translocation is not fully elucidated, it is our hope that documentation of this patient's presentation will help to characterize the significance of a yet undefined cytogenetic abnormality in AML.

Regional techniques for head and neck surgical procedures.

Regional anesthesia has evolved as an important tool for anesthesiologists and surgeons managing patients for surgery of the head and neck region. In recent years, ultrasound use has increased significantly, and newer nerve blocks have been established for surgeries of the head and regions. In this review, anatomy, indications, efficacy, and potential side effects of regional anesthesia for the head and neck region are presented. Evolving practice strongly suggests that regional nerve blocks for the head and neck region are safe and effective. Future studies and education will likely evolve practice to make these regional techniques standards for future surgeries of the head and neck region.