Comparison of split thickness skin graft versus full thickness skin graft for radial forearm flap donor site closure: A systematic review and Meta-analysis.

BACKGROUND: The radial forearm flap (RFF) is one of the most commonly used flaps in reconstructive surgery. Split-thickness skin grafting (STSG) has traditionally been used for closure of the forearm. However, full-thickness skin grafting (FTSG) has gained in popularity to achieve more satisfactory results. The aim of the study is to identify the best RFF donor site closure technique by comparing the functional and aesthetic outcomes of STSG and FTSG. METHODS: PubMed and EMBASE databases were queried. Only studies comparing complications rate, functional and aesthetic outcomes between STSG and FTSG were included. The primary outcome was graft failure rate. Secondary outcomes included the aesthetic result and functionality of the forearm/wrist. RESULTS: A total of 13 studies were included in this review, accounting for a total of 712 patients with mean age of 60.7 years. Overall, 348 patients underwent FTSG and 377 underwent STSG. The mean follow-up was 14.7 months. The rate of graft failure in FTSG was significantly higher compared to STSG (OR: 2.79, 95 % CI 1.38-5.65, p = 0.004). There was no significant difference in rate of tendon exposure (OR: 0.83, p = 0.65) and infection (OR: 1.37, p = 0.42). Regarding the aesthetic outcome, no significant difference between FTSG and STSG based on observer (SMD = -0.37, p = 0.17) and patient (SMD = -0.016, p = 0.93) assessment, respectively. Overall postoperative functional assessment showed a not severely impaired hand and arm function in both groups. Subjective evaluation of pain was similar between groups. CONCLUSION: FTSG is associated with higher risk of graft failure than STSG in RFF donor site closure, without significant improvement in aesthetic results.

A Longitudinal Analysis of Pre- and Post-Operative Dysmorphology in Metopic Craniosynostosis.

OBJECTIVE: The purpose of this study is to objectively quantify the degree of overcorrection in our current practice and to evaluate longitudinal morphological changes using CranioRateTM, a novel machine learning skull morphology assessment tool.  . DESIGN: Retrospective cohort study across multiple time points. SETTING: Tertiary care children's hospital. PATIENTS: Patients with preoperative and postoperative CT scans who underwent fronto-orbital advancement (FOA) for metopic craniosynostosis. MAIN OUTCOME MEASURES: We evaluated preoperative, postoperative, and two-year follow-up skull morphology using CranioRateTM to generate a Metopic Severity Score (MSS), a measure of degree of metopic dysmorphology, and Cranial Morphology Deviation (CMD) score, a measure of deviation from normal skull morphology. RESULTS: Fifty-five patients were included, average age at surgery was 1.3 years. Sixteen patients underwent follow-up CT imaging at an average of 3.1 years. Preoperative MSS was 6.3 ± 2.5 (CMD 199.0 ± 39.1), immediate postoperative MSS was -2.0 ± 1.9 (CMD 208.0 ± 27.1), and longitudinal MSS was 1.3 ± 1.1 (CMD 179.8 ± 28.1). MSS approached normal at two-year follow-up (defined as MSS = 0). There was a significant relationship between preoperative MSS and follow-up MSS (R2 = 0.70). CONCLUSIONS: MSS quantifies overcorrection and normalization of head shape, as patients with negative values were less "metopic" than normal postoperatively and approached 0 at 2-year follow-up. CMD worsened postoperatively due to postoperative bony changes associated with surgical displacements following FOA. All patients had similar postoperative metopic dysmorphology, with no significant association with preoperative severity. More severe patients had worse longitudinal dysmorphology, reinforcing that regression to the metopic shape is a postoperative risk which increases with preoperative severity.

Upper Extremity Functional Outcomes After Breast Cancer Treatment: An Analysis of DASH Score in Breast Reconstruction Patients.

BACKGROUND: Patients undergoing postoncologic breast reconstruction can experience upper extremity (UE) functional deficits. OBJECTIVES: In this study, we utilized the disabilities of the arm, shoulder, and hand (DASH) questionnaire to identify patient factors that impacted UE functional recovery. METHODS: Patients who underwent oncologic followed by reconstructive surgery by a single surgeon from 2014 to 2019 and completed the DASH survey were included. A DASH score was calculated for each patient, with values ranging from 0 (no impairment) to 100 (severe impairment). Regression analysis was conducted to identify significant predictors for DASH score with a significance level for entry and stay set at P = .15. RESULTS: Among 289 patients who underwent breast reconstruction, 157 completed the questionnaire. The average patient age was 52.6yrs ± 8.6 at the time of reconstruction. A total of 111 had implant-based reconstruction, 15 had autologous reconstruction, and 24 had a combination of both. Average DASH score was 7.7 (range 0.0-52.5), with 74.1% of patients having a score greater than 0. Regression analysis showed 5 variables associated with significantly higher DASH scores: age between 50 and 60 years (P = .13), history of radiation (P = .01), placement of a subpectoral implant (P = .06), postoperative complications (P = .10), and lymphedema (P < .01). Autologous breast reconstruction (P = .04) was associated with a significantly lower DASH score. CONCLUSIONS: Implant-based reconstruction, radiation history, postoperative complications, and age at reconstruction were associated with increased UE functional impairment in patients who underwent breast reconstructive surgery. Identification of these factors can inform areas for potential practice changes and improve patient counseling regarding postoperative expectations.

The Biosimilar Paradox: How Anti-Vascular Endothelial Growth Factor Biosimilars Could Increase Patient and Overall Health Care Costs.

PURPOSE: Anti-vascular endothelial growth factor (VEGF) medications for intraocular use are a major and increasing cost, and biosimilars may be a means of reducing the high cost of many biologic medications. However, a bevacizumab biosimilar, which is currently pending Food and Drug Administration (FDA) approval (bevacizumab-vikg), paradoxically may increase the cost burden of intravitreal anti-VEGF agents, because off-label repackaged drugs may no longer be allowed per the Drug Quality and Security Act (DQSA). We aimed to investigate the potential impact of biosimilars on costs in the United States. DESIGN: Cost analysis of anti-VEGF medications. PARTICIPANTS: Medicare data from October 2022 and previously published market share data from 2019. METHODS: Average sales prices (ASPs) of ranibizumab, aflibercept, and bevacizumab were calculated from Medicare allowable payments. The ASPs of biosimilars were calculated from wholesale acquisition costs from a representative distributor. The cost of an intraocular bevacizumab formulation is modeled at $500/1.25-mg dose and $900/1.25-mg dose. MAIN OUTCOME MEASURES: Costs of anti-VEGF drugs to Medicare Part B and patients. RESULTS: If an intraocular bevacizumab biosimilar were to be priced at $500, costs to Medicare would increase by $457 million from $3.01 billion to $3.47 billion (15.2% increase). Patient responsibility would increase by $117 million from $768 million to $884 million. Similarly, if intraocular bevacizumab were priced at $900, Medicare costs would increase by $897 million to $3.91 billion (29.8% increase), and patient responsibility would increase by $229 million to $997 million. If bevacizumab were $500/dose, switching all patients currently receiving ranibizumab or aflibercept to respective biosimilars would compensate for only 28.8% of the increased cost. Current prices of ranibizumab and aflibercept biosimilars would have to decrease by an aggregate of 15.7% to $616.80/injection, $1027.97/injection, and $1436.88/injection for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept, respectively. CONCLUSIONS: An FDA-approved bevacizumab biosimilar for ophthalmic use could increase costs to the health care system and patients, raising concerns for access. This increase would not be offset by ranibizumab and aflibercept biosimilar use at current prices. These data support the need for an exemption of section 503B of the DQSA and continued use of repackaged off-label bevacizumab. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluation of Perioperative Versus Extended Courses of Antibiotic Prophylaxis After Immediate Implant-Based Breast Reconstruction.

BACKGROUND: Immediate implant-based breast reconstruction (IIBR) is the most commonly used method in breast reconstruction in the United States. However, postoperative surgical site infections (SSIs) can cause devastating reconstructive failure. This study evaluates the use of perioperative versus extended courses of antibiotic prophylaxis after IIBR for the prevention of SSI. METHODS: This is a single-institution retrospective study of patients who underwent IIBR between June 2018 and April 2020. Detailed demographic and clinical information was collected. Patients were divided into subgroups based on antibiotic prophylaxis regimen: group 1 consisted of patients who received 24 hours of perioperative antibiotics and group 2 consisted of patients who received ≥7 days of antibiotics. Statistical analyses were conducted using SPSSv26.0 with P ≤ 0.05 considered statistically significant. RESULTS: A total of 169 patients (285 breasts) who underwent IIBR were included. The mean age was 52.4 ± 10.2 years, and the mean body mass index (BMI) was 26.8 ± 5.7 kg/m2. Twenty-five percent of patients (25.6%) underwent nipple-sparing mastectomy, 69.1% skin-sparing mastectomy, and 5.3% total mastectomy. The implant was placed in the prepectoral, subpectoral, and dual planes in 16.7%, 19.2%, and 64.1% cases, respectively. Acellular dermal matrix was used in 78.7% of cases. A total of 42.0% of patients received 24-hour prophylaxis (group 1), and 58.0% of patients received extended prophylaxis (group 2). Twenty-five infections (14.8%) were identified, of which 9 (5.3%) resulted in reconstructive failure. In bivariate analyses, no significant difference was found between groups in rates of infection (P = 0.273), reconstructive failure (P = 0.653), and seroma (P = 0.125). There was a difference in hematoma rates between groups (P = 0.046). Interestingly, in patients who received only perioperative antibiotics, infection rates were significantly higher in those with BMI ≥ 25 (25.6% vs 7.1%, P = 0.050). There was no difference in overweight patients who received extended antibiotics (16.4% vs 7.0%, P = 0.160). CONCLUSIONS: Our data demonstrate no statistical difference in infection rates between perioperative and extended antibiotics. This suggests that the efficacies of current prophylaxis regimens are largely similar, with choice of regimen based on surgeon preference and patient-specific considerations. Infection rates in patients who received perioperative prophylaxis and were overweight were significantly higher, suggesting that BMI should be taken into consideration when choosing a prophylaxis regimen.

Analyzing the Impact of Social and Psychiatric Factors in Patients Who Undergo Body Contouring Procedures.

BACKGROUND: As the prevalence of obesity increases, the number of patients seeking body contouring procedures after bariatric surgery for massive weight loss is increasing. Although the positive impact of bariatric surgery on physical and emotional health is well-described, few studies have reported on the psychosocial well-being of patients undergoing body contouring procedures. Psychosocial well-being can impact patient satisfaction and maintenance of weight loss, and is an important area to study. OBJECTIVE: The aim of this study was to characterize social and psychiatric factors of patients undergoing body contouring surgery, and to evaluate their impact on maintenance of weight loss. METHODS: A retrospective review was performed of patients who presented to a single institution for body contouring procedures between 2002 and 2018. Demographic details, medical history, psychosocial support, and operative details were collected. Univariate analysis and multinomial logistic regressions were performed with R statistical software (version 1.3.1093). RESULTS: A total of 1187 patients underwent at least 1 body contouring procedure during the study time frame. Mean BMI at presentation was 31.21 ± 10.49 kg/m2. Patients diagnosed with obesity at age 18 or older had significantly greater odds of suffering from generalized anxiety disorder (odds ratio [OR] 1.08 [95% CI, 1.02-1.15], P = .008). Patients with spousal support had 1.93 times higher odds of having maintained postbariatric weight loss at their 6-month follow-up (OR 1.93 [95% CI, 1.84-2.01], P = .028). CONCLUSIONS: Social support and age of obesity diagnosis impact psychological well-being and maintenance of weight loss following body contouring procedures.

Preoperative blood pressure and risk of delayed graft function in deceased donor kidney transplantation.

BACKGROUND: In kidney transplantation, delayed graft function (DGF) is associated with increased morbidity and a higher risk of graft failure. Prior research suggests that chronic hypotension increases DGF risk, but the relationship of preoperative blood pressure to DGF is unclear. METHODS: In this single center study of adult deceased donor kidney transplant recipients transplanted between 2015 and 2019, we evaluated the question of whether preoperative mean arterial pressure (MAP) affected DGF risk. Additionally, we investigated whether the risk of DGF was moderated by certain donor and recipient characteristics. For recipient characteristics associated with increased DGF risk and preoperative MAP, we performed a mediation analysis to estimate the proportion of DGF risk mediated through preoperative MAP. RESULTS: Among 562 deceased donor kidney recipients, DGF risk decreased as preoperative MAP increased, with a 2% lower risk per 1 mm Hg increase in MAP. This increased risk was similar, with no statistically significant interaction effect between preoperative MAP and donor (donation after circulatory death) and recipient characteristics (diabetes, body mass index, and use of anti-hypertensive medications). Preoperative MAP was negativity correlated with recipient BMI and duration of pre transplant dialysis. On mediation analysis, MAP accounted for 12% and 16% of the DGF risk associated with recipient BMI and pre-transplant dialysis duration, respectively. CONCLUSION: In deceased donor kidney transplantation, each 1 mm Hg increase in preoperative MAP was associated with 2% lower DGF risk. Preoperative MAP was influenced by recipient BMI and dialysis duration, and likely contributes to some of the high DGF risk from obesity and long dialysis vintage.

SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain.

SLC26A9, a member of the solute carrier protein family, transports chloride ions across various epithelia. SLC26A9 also associates with other ion channels and transporters linked to human health, and in some cases these heterotypic interactions are essential to support the biogenesis of both proteins. Therefore, understanding how this complex membrane protein is initially folded might provide new therapeutic strategies to overcome deficits in the function of SLC26A9 partners, one of which is associated with Cystic Fibrosis. To this end, we developed a novel yeast expression system for SLC26A9. This facile system has been used extensively with other ion channels and transporters to screen for factors that oversee protein folding checkpoints. As commonly observed for other channels and transporters, we first noted that a substantial fraction of SLC26A9 is targeted for endoplasmic reticulum associated degradation (ERAD), which destroys folding-compromised proteins in the early secretory pathway. We next discovered that ERAD selection requires the Hsp70 chaperone, which can play a vital role in ERAD substrate selection. We then created SLC26A9 mutants and found that the transmembrane-rich domain of SLC26A9 was quite stable, whereas the soluble cytosolic STAS domain was responsible for Hsp70-dependent ERAD. To support data obtained in the yeast model, we were able to recapitulate Hsp70-facilitated ERAD of the STAS domain in human tissue culture cells. These results indicate that a critical barrier to nascent membrane protein folding can reside within a specific soluble domain, one that is monitored by components associated with the ERAD machinery.

Revision Pharyngoplasty in Cleft Palate and Velopharyngeal Insufficiency: Management and Outcomes.

INTRODUCTION: Velopharyngeal insufficiency (VPI), a stigmatizing hallmark of palatal dysfunction, occurs in a wide spectrum of pediatric craniofacial conditions. The mainstays for surgical correction include palate repair and/or pharyngeal surgery. However, primary pharyngoplasty has a failure rate of 15% to 20%. Although revision pharyngoplasty may be necessary in those with persistent VPI, little is known regarding the indications for and outcomes after such procedures. The purpose of this study is to describe the authors' experience with indications for and outcomes after revision pharyngoplasty. METHODS: A single-center retrospective review was performed of all patients undergoing revision pharyngoplasty between 2002 and 2019. Demographic data and Pittsburgh Weighted Speech Scores, diagnoses, comorbidities, and complications were tabulated. Two-tailed Student t test was used, and a P value of 0.05 or less was considered statistically significant. RESULTS: Thirty-two patients (65.6% male) met inclusion criteria for this study. The most common diagnoses included cleft palate (68.8%), submucous cleft palate (SMCP, 18.8%), and congenital VPI (6.3%, likely occult SMCP). Most patients (84.4%) underwent palatoplasty before their initial pharyngoplasty. The primary indication for initial pharyngoplasty was VPI (mean age 7.1 ± 4.6 years). The most common indication for revision pharyngoplasty (mean age 11.2 ± 5.1 years) included persistent VPI (n = 22), followed by obstructive sleep apnea (OSA) (n = 11). Persistent VPI (n = 8) and OSA (n = 6) were the most common complications after secondary pharyngoplasty. Thirteen patients (40.6%) within the revision pharyngoplasty cohort required additional surgical intervention: 4 underwent tertiary pharyngoplasty, 4 underwent takedown for OSA (n = 3) or persistent VPI (n = 1), 3 underwent takedown and conversion Furlow for persistent VPI (n = 2), OSA (n = 2) and/or flap dehiscence (n = 1), and 2 underwent palatal lengthening with buccal myomucosal flaps for persistent VPI. Of the 4 patients who required a tertiary pharyngoplasty, the mean age at repair was 6.6 ± 1.1 years and their speech scores improved from 13.5 to 2.3 after tertiary pharyngoplasty (P = 0.11). The overall speech score after completion of all procedures improved significantly from 19 to 3.3. CONCLUSION: Patients who fail primary pharyngoplasty represent a challenging population. Of patients who underwent secondary pharyngoplasty, nearly half required a tertiary procedure to achieve acceptable speech scores or resolve complications.

Geographic Atrophy Natural History Versus Treatment: Time to Fovea.

BACKGROUND AND OBJECTIVE: The Food and Drug Administration recently approved treatments of geographic atrophy (GA). Our study aims to quantify the time for a lesion to reach the central fovea based on reduction of GA growth rates from therapeutics compared to the natural history. PATIENTS AND METHODS: A previously published study calculates local border expansion rate of GA lesions at varying retinal eccentricities. In this study, we use these rates to model GA expansion toward the fovea and the effects of treatments that reduce growth in GA area by 15% to 45% on lesions of varying sizes with posterior margin 250, 500, 750, 1000, 1250, 1500, and 3000 µm from the fovea. RESULTS: Lesions with an area 8 mm2 and posterior edge 500 µm from the fovea will reach the fovea in 5.08 years with no treatment, but the same lesions will reach the fovea in 5.85, 6.52, 7.36, and 8.46 years with a treatment that reduces growth in GA area by 15%, 25%, 35%, and 45%, respectively. CONCLUSIONS: Distance of the posterior edge of the lesion was the primary factor in GA growth toward the fovea, and lesion size only minimally affects growth rates of GA. Based on the efficacy of current and future therapeutics and distance of GA to the fovea, our study provides the marginal time benefit of treatment to guide patients and clinicians, placing both the natural history of GA and the effects of current and future treatments into clinical context. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

High-resolution structures with bound Mn2+ and Cd2+ map the metal import pathway in an Nramp transporter.

Transporters of the Nramp (Natural resistance-associated macrophage protein) family import divalent transition metal ions into cells of most organisms. By supporting metal homeostasis, Nramps prevent diseases and disorders related to metal insufficiency or overload. Previous studies revealed that Nramps take on a LeuT fold and identified the metal-binding site. We present high-resolution structures of Deinococcus radiodurans (Dra)Nramp in three stable conformations of the transport cycle revealing that global conformational changes are supported by distinct coordination geometries of its physiological substrate, Mn2+, across conformations, and by conserved networks of polar residues lining the inner and outer gates. In addition, a high-resolution Cd2+-bound structure highlights differences in how Cd2+ and Mn2+ are coordinated by DraNramp. Complementary metal binding studies using isothermal titration calorimetry with a series of mutated DraNramp proteins indicate that the thermodynamic landscape for binding and transporting physiological metals like Mn2+ is different and more robust to perturbation than for transporting the toxic Cd2+ metal. Overall, the affinity measurements and high-resolution structural information on metal substrate binding provide a foundation for understanding the substrate selectivity of essential metal ion transporters like Nramps.

Late-Presenting Sagittal Craniosynostosis: An Update to a Standardized Treatment Protocol.

BACKGROUND: The authors previously published their protocol to treat patients who present with sagittal craniosynostosis after the age of 1 year. The purpose of this article is to present a follow-up and update of this cohort to evaluate outcomes of their treatment protocol. METHODS: Patients with isolated sagittal craniosynostosis who presented after the age of 1 year between July of 2013 and April of 2021 were included. RESULTS: A total of 108 patients met inclusion criteria. The average age at presentation was 5.2 ± 3.4 years, and 79 patients (73.1%) were male. The indications for imaging were head shape (54.6%), headache (14.8%), trauma (9.3%), seizure (4.6%), papilledema (2.8%), and other (13.9%). Of the 108 patients, 12 (11.1%) underwent surgery following their initial consultation: five for papilledema, four for elevated intracranial pressure, two for severely scaphocephalic head shapes, and one for abnormal funduscopic findings. Two of these patients underwent additional reconstructive surgery, one for the recurrence of papilledema and headache and the other for progressive scaphocephaly. The average length of time between operations was 4.9 years. Of the 96 patients who were managed conservatively, four (4.2%) underwent surgery at an average of 1.2 ± 0.5 years later (average age, 4.4 ± 1.5 years) for brain growth restriction ( n = 2), aesthetic concerns ( n = 1), and refractory headaches ( n = 1). The average follow-up of all patients with craniofacial surgery was 2.7 ± 2.3 years (median, 2.1 years; interquartile range, 3.7 years). CONCLUSIONS: Patients with late-presenting sagittal craniosynostosis require surgical correction less often than younger patients, likely because of milder phenotype. Few patients in the conservative treatment arm ultimately required surgery (4%). CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Structural Basis of AZD9291 Selectivity for EGFR T790M.

AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met 790) in T790M but not with Thr 790 in the WT, which explains why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that can overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses.

Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter.

Nramp family transporters-expressed in organisms from bacteria to humans-enable uptake of essential divalent transition metals via an alternating-access mechanism that also involves proton transport. We present high-resolution structures of Deinococcus radiodurans (Dra)Nramp in multiple conformations to provide a thorough description of the Nramp transport cycle by identifying the key intramolecular rearrangements and changes to the metal coordination sphere. Strikingly, while metal transport requires cycling from outward- to inward-open states, efficient proton transport still occurs in outward-locked (but not inward-locked) DraNramp. We propose a model in which metal and proton enter the transporter via the same external pathway to the binding site, but follow separate routes to the cytoplasm, which could facilitate the co-transport of two cationic species. Our results illustrate the flexibility of the LeuT fold to support a broad range of substrate transport and conformational change mechanisms.