Meta-Analysis and Meta-Regression of Complications and Failures of Autologous Heterotopic Cranial Bone versus Alloplastic Cranioplasties.

BACKGROUND: Fresh autologous cranial bone graft has been traditionally regarded as the ideal cranioplasty material, however long-term comparisons of outcomes with modern alloplastic materials are absent in the literature. In this work, we evaluated complications and failures among cranioplasties performed with fresh, heterotopic, cranial bone graft versus three common alloplastic materials. METHODS: Random-effects meta-analyses of logit-transformed proportions were performed on studies published between 1971-2021 to evaluate complications and failures of cranioplasties performed with fresh, autologous, heterotopic cranial bone, polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), or titanium with a mean follow-up ≥12 months. Generalized mixed model meta-regressions were performed to account for heterogeneity and to evaluate the contributions of moderators to outcomes variables. RESULTS: 1490 patients (mean age 33.9±10.8 years) were included. Pooled, all-cause complications were 6.2% for fresh, heterotopic, autologous cranial bone (95% confidence interval [CI]:2.1-17.0%; I2=55.0%, p=0.02), 18.5% for PEEK (95%CI:14.0-24.0%; I2=0.0%, p=0.58), 26.1% for titanium (95%CI:18.7-35.1%; I2=60.6%, p<0.01), and 28.4% for PMMA (95%CI:12.9-51.5%; I2=88.5%, p<0.01). Pooled all-cause failures were 2.2% for fresh, autologous cranial bone (95%CI:0.4-10.6%; I2=0.0%, p=0.45), 6.3% for PEEK (95%CI:3.2-12.3%; I2=15.5%, p=0.31), 11.4% for titanium (95%CI:6.7-18.8%; I2=60.8%, p<0.01), and 12.7% for PMMA (95%CI:6.9-22.0%; I2=64.8%, p<0.01). Meta-regression models indicated that each alloplastic subtype significantly and independently predicted higher complications, while titanium and PMMA were significant predictors for all-cause failures compared to autologous bone. All three subtypes were predictive of higher cranioplasty failures secondary to infection compared to autologous bone. CONCLUSIONS: Cranioplasties performed with fresh, autologous heterotopic cranial bone grafts resulted in lower complications and failures compared to alloplastic materials.

An enhanced recovery after surgery protocol for facial feminization surgery reduces perioperative opioid usage, pain, and hospital stay.

BACKGROUND: Prescription drug misuse in transgender individuals is estimated to be three times higher than that of the general population in the United States, suggesting that opioid-reduction strategies deserve significant consideration in gender-affirming surgeries. In this work, we describe the implementation of an enhanced recovery after surgery (ERAS) protocol to reduce opioid use after facial feminization surgery. METHODS: A total of 79 patients who underwent single-stage facial feminization surgery before (n = 38) or after (n = 41) ERAS protocol implementation were included. Primary outcomes assessed were perioperative opioid consumption (morphine equivalent dose/kilogram, MED/kg), average patient-reported pain scores, and length of hospital stay. Comparisons between groups and multivariable linear regression analyses were conducted to define the contribution of the ERAS protocol to each of the three primary outcomes. RESULTS: Age, body mass index, mental health diagnoses, and length of surgery did not differ between pre-ERAS and ERAS groups. Compared to pre-ERAS patients, patients treated under the ERAS protocol consumed less opioids (median [interquartile range, IQR], 0.8 [0.5-1.1] versus 1.5 [1.0-2.1] MED/kg, p < 0.001), reported lower pain scores (2.5 ± 1.8 versus 3.7 ± 1.6, p = 0.002), and required a shorter hospital stay (median [IQR], 27.3 [26.3-49.8] versus 32.4 [24.8-39.1] h, p < 0.001). When controlling for other contributing variables such as previous gender-affirming surgeries, mental health diagnoses, and length of surgery using multivariable linear regression analyses, ERAS protocol implementation independently predicted reduced opioid use, lower pain scores, and shorter hospital stay after facial feminization surgery. CONCLUSIONS: The current work details an ERAS protocol for facial feminization surgery that reduces perioperative opioid consumption, patient-reported pain scores, and hospital stays.

Association of Patient-Reported Anxiety and Pain After Alveolar Bone Grafting.

OBJECTIVE: To evaluate the role of psychosocial well-being on perioperative pain and opioid use among patients with cleft lip and palate (CLP) undergoing alveolar bone grafting (ABG). DESIGN: Retrospective review. SETTING: Tertiary level craniofacial clinic. PARTICIPANTS: 34 patients with CLP (median age: 11.7 years), including 25 (73.5%) unilateral CLP and 9 (26.5%) bilateral CLP, who underwent ABG from 2015 to 2022. INTERVENTIONS: ABG using iliac crest bone graft. Patients were prospectively administered four patient-reported psychosocial instruments from the Patient-Reported Outcomes Measurement Information System. MAIN OUTCOME MEASURES: Perioperative opioid use in morphine equivalent dosage/kilogram, patient-reported pain scores, and length of hospital stay after ABG. RESULTS: Patient-reported anxiety (r = 0.41, p = 0.02) and depressive symptoms (r = 0.35, p = 0.04) correlated to higher perioperative opioid usage. Multivariable regression models including psychosocial scores, total acetaminophen usage, length of surgery, and other simultaneous surgeries were developed for total opioid usage, patient-reported pain, and length of hospital stay. Patient-reported anxiety was independently predictive of higher perioperative opioid use (ß=0.36, p = 0.01) and higher pain scores (ß=0.39, p = 0.02), but not length of hospital stay. CONCLUSIONS: We identified an association for patient-reported anxiety and perioperative opioid use and pain in a CLP cohort undergoing ABG. Future considerations in preoperative patient and family consultation may be indicated in patients self-reporting higher anxiety in an effort to minimize perioperative opioid usage.

Modulating Temporospatial Phosphate Equilibrium by Nanoparticulate Mineralized Collagen Materials Induces Osteogenesis via PiT-1 and PiT-2.

The temporospatial equilibrium of phosphate contributes to physiological bone development and fracture healing, yet optimal control of phosphate content has not been explored in skeletal regenerative materials. Nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) is a synthetic, tunable material that promotes in vivo skull regeneration. In this work, the effects of MC-GAG phosphate content on the surrounding microenvironment and osteoprogenitor differentiation are investigated. This study finds that MC-GAG exhibits a temporal relationship with soluble phosphate with elution early in culture shifting to absorption with or without differentiating primary bone marrow-derived human mesenchymal stem cells (hMSCs). The intrinsic phosphate content of MC-GAG is sufficient to stimulate osteogenic differentiation of hMSCs in basal growth media without the addition of exogenous phosphate in a manner that can be severely reduced, but not eliminated, by knockdown of the sodium phosphate transporters PiT-1 or PiT-2. The contributions of PiT-1 and PiT-2 to MC-GAG-mediated osteogenesis are nonredundant but also nonadditive, suggestive that the heterodimeric form is essential to its activity. These findings indicate that the mineral content of MC-GAG alters phosphate concentrations within a local microenvironment resulting in osteogenic differentiation of progenitor cells via both PiT-1 and PiT-2.

Osteoprotegerin-eluting nanoparticulate mineralized collagen scaffolds improve skull regeneration.

Custom synthesis of extracellular matrix (ECM)-inspired materials for condition-specific reconstruction has emerged as a potentially translatable regenerative strategy. In skull defect reconstruction, nanoparticulate mineralized collagen glycosaminoglycan scaffolds (MC-GAG) have demonstrated osteogenic and anti-osteoclastogenic properties, culminating in the ability to partially heal in vivo skull defects without the addition of exogenous growth factors or progenitor cell loading. In an effort to reduce catabolism during early skull regeneration, we fabricated a composite material (MCGO) of MC-GAG and recombinant osteoprotegerin (OPG), an endogenous anti-osteoclastogenic decoy receptor. In the presence of differentiating osteoprogenitors, MCGO demonstrated an additive effect with endogenous OPG limited to the first 14 days of culture with total eluted and scaffold-bound OPG exceeding that of MC-GAG. Functionally, MCGO exhibited similar osteogenic properties as MC-GAG, however, MCGO significantly reduced maturation and resorptive activities of primary human osteoclasts. In a rabbit skull defect model, MCGO scaffold-reconstructed defects displayed higher mineralization as well as increased hardness and microfracture resistance compared to non-OPG functionalized MC-GAG scaffolds. The current work suggests that MCGO is a development in the goal of reaching a materials-based strategy for skull regeneration.

Effect of Gender-affirming Facial Feminization Surgery on Psychosocial Outcomes.

OBJECTIVE: This study investigates the effect of gender-affirming facial feminization surgery (FFS) on psychosocial outcomes in patients with gender dysphoria. BACKGROUND: Comprehensive analyses of psychosocial outcomes after gender-affirming FFS are absent in the literature resulting in a paucity of information on the impact of FFS on quality of life as well as ramifications in health insurance coverage of FFS. METHODS: Scores from 11 validated, quantitative instruments from the Patient-Reported Outcomes Measurement Information System (PROMIS) assessing anxiety, anger, depression, global mental health, global physical health, satisfaction with sex life, positive affect, emotional support, social isolation, companionship, and meaning and purpose. Patients within the preoperative group (pre-FFS) were evaluated >30 days before surgery and patients within the postoperative group (post-FFS) were evaluated ≥10 weeks after surgery. RESULTS: A total of 169 patients [mean (SD) age, 33.5 (10.8) years] were included. Compared with the pre-FFS group (n=107), the post-FFS group (n=62) reported improved scores anxiety (56.8±8.8 vs 60.1±7.9, P =0.01), anger (47.4±7.6 vs 51.2±9.6, P =0.01), depression (52.2±9.2 vs 57.0±8.9, P =0.001), positive affect (46.6±8.9 vs 42.9±8.7, P =0.01), meaning and purpose (49.9±10.7 vs 46.2±10.5, P =0.03), global mental health (46.7±7.6 vs 43.1±9.2, P =0.01), and social isolation (52.2±7.5 vs 55.4±7.4, P =0.01). Multivariable analysis to account for the effects of other gender-affirming surgeries, hormone therapy duration, preexisting mental health diagnoses, socioeconomic disparities, and patient-reported quality of social relationships on psychosocial functioning demonstrated that completion of FFS was independently predictive of improved scores. CONCLUSIONS: Gender-affirming FFS improves the quality of life by multiple psychosocial domains in transfeminine patients.

Hearing Preservation in a Vestibular Schwannoma Patient via a Retrosigmoid Approach.

Vestibular schwannoma(s) (VS) are benign tumors of the cerebellopontine angle comprising the Schwann cells that line the vestibular branch of cranial nerve VIII. Treatment goals focus on the preservation and improvement of facial nerve and hearing function as well as tumor control. The retrosigmoid (RS) approach is associated with lower hearing preservation rates compared to the middle cranial fossa (MCF) approach. A 60-year-old male was diagnosed with right-sided cystic VS and subsequently underwent surgical resection via a RS approach. Although his preoperative hearing function was quite low, with a right-sided speech reception threshold of 35 dB and a right-sided word recognition score of 48%, he experienced a drastic improvement in his hearing postoperatively with stable residual tumor. Although the RS approach for VS resection is not considered to be as effective at preserving hearing function compared to the MCF approach, we present a case where it resulted in significantly improved hearing function. Additionally, in cases where preoperative hearing function is severely diminished, hearing preservation is not typically an outcome that is considered. However, this case suggests that improvement of hearing in these patients may be attainable, particularly with the RS approach.

Systematic Review of Serum Biomarkers in Traumatic Brain Injury.

Traumatic brain injury (TBI) is responsible for the majority of trauma-related deaths and is a leading cause of disability. It is characterized by an inflammatory process involved in the progression of secondary brain injury. TBI is measured by the Glasgow Coma Scale (GCS) with scores ranging from 15-3, demonstrating mild to severe brain injury. Apart from this clinical assessment of TBI, compendiums of literature have been published on TBI-related serum markers.Herein we create a comprehensive appraisal of the most prominent serum biomarkers used in the assessment and care of TBI.The PubMed, Scopus, Cochrane, and Web of Science databases were queried with the terms "biomarker" and "traumatic brain injury" as search terms with only full-text, English articles within the past 10 years selected. Non-human studies were excluded, and only adult patients fell within the purview of this analysis. A total of 528 articles were analyzed in the initial search with 289 selected for screening. A further 152 were excluded for primary screening. Of the remaining 137, 54 were included in the final analysis. Serum biomarkers were listed into the following broad categories for ease of discussion: immune markers and markers of inflammation, hormones as biomarkers, coagulation and vasculature, genetic polymorphisms, antioxidants and oxidative stress, apoptosis and degradation pathways, and protein markers. Glial fibrillary acidic protein(GFAP), S100, and neurons specific enolase (NSE) were the most prominent and frequently cited markers. Amongst these three, no single serum biomarker demonstrated neither superior sensitivity nor specificity compared to the other two, therefore noninvasive panels should incorporate these three serum biomarkers to retain sensitivity and maximize specificity for TBI.

Systematic review and evaluation of predictive modeling algorithms in spinal surgeries.

In order to better educate patients, predictive models have been implemented to stratify surgical risk, thereby instituting greater uniformity across surgical practices and prioritizing the safety and outcomes of patients. The purpose of this study is to conduct a systematic review summarizing the major predictive models used to evaluate patients as candidates for spinal surgery. A search was conducted for articles related to predictive modeling in spinal surgeries using PubMed, MEDLINE, and Scopus databases. Papers with area under the receiver operating curve (AUROC) scores reported were included in the analysis. Models not relevant to spinal procedures were excluded. Comparison between models was only attainable for those that reported AUROCs for individual procedures. Based on a combination of AUROC scores and demonstrated applicability to spinal procedures, the models by Scheer et al. (0.89), Ratliff et al. (0.70), the Seattle Spine Score (0.712), Risk Assessment Tool (0.67-0.7), and the Spine Sage calculator (0.81-0.85) were determined to be ideal for predictive modeling in spinal surgeries and were subsequently broken down into their individual inputs and outputs to determine what elements a theoretical model should assimilate. Alongside the model by Scheer et al., the Spine Sage calculator, Seattle Spine Score, Risk Assessment Tool, and a model by Ratliff et al. showed the most promise for patients undergoing spinal procedures. Using the first model as a springboard, new spinal predictive models can be optimized through use of larger prospective databases, with longer follow-up times, and greater inclusion of reliable high impact variables.

A systematic analysis of stereotactic radiosurgery surveys for residents in neurosurgery training programs.

OBJECT: The use of stereotactic radiosurgery (SRS) has increased. SRS training has not risen congruently. Neurosurgeons have conducted surveys and advocated implementation of widespread, standardized radiosurgery training. Here we analyze the SRS surveys conducted throughout the past decade. METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic literature review. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, and Web of Science databases. This study included surveys evaluating SRS training in neurosurgery and excluded those regarding other specialties. RESULTS: An overview of surveys showed that neurosurgery residents possess gaps in SRS knowledge and procedural competency that have persisted through the past decade. There is an overwhelming sentiment that current radiosurgery training is not adequate to prepare residents for future practice. Our recommendation is for residency programs to integrate formal SRS training electives, with a movement towards creating more options for extended SRS fellowships post-residency. CONCLUSIONS: We present data from SRS competency and current training surveys. Although resident SRS training still lags behind other subspecialties, we see indications for growth. To keep up with the role of SRS in neurosurgery, residencies need more formalized SRS rotations.

Meta-analysis of tumor control rates in patients undergoing stereotactic radiosurgery for cystic vestibular schwannomas.

OBJECTIVE: The use of SRS for treatment of cystic vestibular schwannoma is a topic of mild controversy. This review serves to introduce a renewed understanding of the efficacy of SRS as a viable treatment modality for cystic VS. PATIENTS AND METHODS: This study was conducted in accordance with the PRISMA guidelines. A broad search of the literature was conducted in October 2018 through the PubMed, Scopus, Embase, Web of Science, and Cochrane databases. Meta-analysis was conducted on tumor control rates and heterogeneity between articles was assessed using τ2, Cochran's Q, and I2 statistics. RESULTS: A total of 246 patients underwent SRS for cystic VS, with reported mean or median follow-up ranging from 49.7 to 150 months, and an overall range of 6-201 months. Following SRS treatment for cystic VS across all studies, 92% of patients had tumor control at follow up, (95%-CI: 88-95%). Tumor control rate specifically for patients who underwent GammaKnife was 93% (95-CI: 88%-95%). CONCLUSION: Despite the paucity of pertinent data, the results of our meta-analysis suggest that SRS exhibits effective tumor control rates in patients with cystic VS. Therefore, SRS can be considered a viable treatment modality when choosing amongst interventions for cystic VS.

Radiosurgery treatment is associated with improved facial nerve preservation versus repeat resection in recurrent vestibular schwannomas.

BACKGROUND: Vestibular schwannomas (VSs) are benign neoplasms of the Schwann cells of cranial nerve VIII, and treatment of VS typically involves surgical resection. However, tumor recurrence may necessitate reintervention, and secondary treatment modalities include repeat surgical resection or adjuvant radiosurgery. The purpose of this study is to examine the scientific literature in order to determine whether surgical resection or radiosurgery for recurrent VS results in better tumor control, hearing preservation, and preservation of facial nerve function. METHODS: The PubMed, Scopus, Embase, Cochrane, and Web of Science databases were searched for studies reporting on patients undergoing either radiosurgery or repeat surgical resection after primary surgical resection for recurrent VS. Statistical analyses were performed on the compiled data, primarily outcome data involving tumor control, hearing preservation, and preservation of facial nerve function. RESULTS: We analyzed the data of 15 individual studies involving 359 total patients, and our results reveal that tumor control rates are comparable between adjuvant radiosurgery (91%, CI: 88-94%) and secondary resection (92%, CI 75-98%). However, adjuvant radiosurgery was shown to preserve good facial nerve function better (94%, CI 84-98%) compared to secondary surgical resection (56%, CI 41-69%). CONCLUSION: With comparable tumor control rates and better preservation of good facial nerve function, this study suggests that secondary radiosurgery for recurrent VS is associated with both optimal tumor control and preservation of good facial nerve function.

Age and gender considerations on the symptomology in patients with superior semicircular canal dehiscence: A systematic review and case illustration.

Superior semicircular canal dehiscence (SSCD) is caused by a fistula in the arcuate eminence, creating vestibular and auditory disturbances. We aim to determine the effects of gender and age on symptom prevalence and resolution in patients with SSCD. A Boolean search was conducted through four separate scientific databases. Full-text English articles for SSCD patients, who underwent surgery were included. Demographics and outcomes were extracted. A total of 198 patients were identified, and available for quantitative analysis. Between genders, there were no differences in the prevalence of pre- or post-operative symptomology. Both genders had statistically significant improvement in symptomatology with females experiencing significantly high rates of hearing loss improvement compared to male patients. Compared to their younger cohort, patients over 65 had similar symptom frequencies before and after surgery with similar rates of symptom resolution. SSCD repair is safe and effective for resolving auditory and vestibular symptoms. Gender and age may not be strong predictors of patient presentation or symptom resolution. Gender and age-associated factors may not influence patient outcomes.

Association of Shadowing Program for Undergraduate Premedical Students with Improvements in Understanding Medical Education and Training.

OBJECTIVE: Physician shadowing has become ubiquitous to the premedical experience. However, students without connections to a medical professional are oftentimes forced to reach out to physicians independently from a program. Subsequently, these inquiries may go unanswered as they oftentimes appear unsolicited. The primary goals in the design and development of our program were to increase access to a clinical observership experience at our academic institution utilizing resident physicians as primary supervisors. METHODS: In January 2017, the Educational Shadowing Program (ESP) was established at our institution wherein undergraduate students could shadow within the Pediatric Continuity Clinic (PCC) staffed by pediatric resident physicians. ESP undergraduates shadowed the residents as they performed their history taking and physical exams and as they presented their patients to the attending physicians. Between patient encounters, the students assisted the residents in their administrative work which was completed as needed. ESP students were surveyed at their first orientation meeting and during the final case conference. RESULTS: The pre-participation survey showed that none of the student participants strongly agreed to having a good understanding of what the job of a resident physician entails. By the end of their 30 weeks, the proportion of participants with a strongly perceived understanding increased significantly. The proportion of student respondents that strongly agreed with their understanding of the physician-patient interaction also improved significantly over the study period, from 33% to 78%. Seventy-two percent of the residents surveyed agreed or strongly agreed that they enjoyed having the undergraduates in the clinic, affirming the positive effects of the program on the resident physicians. Forty-five percent of residents agreed or strongly agreed that the undergraduates improved their workflow in the clinic. CONCLUSION: This study demonstrates that establishing an undergraduate shadowing program in a busy academic pediatric clinic that involves resident physicians can be an overall positive experience for all participants. Fostering premedical student interest in pediatric care and primary care can possibly lead to more physician commitment to these fields, potentially helping to alleviate impending physicians in these specialties.

Crystal structure and functional analysis of Leishmania major pseudoperoxidase.

Leishmania major pseudoperoxidase (LmPP) is a recently discovered heme protein expressed by the human pathogen. Previous in vivo and in vitro studies suggest that LmPP is a crucial element of the pathogen's defense mechanism against the reactive nitrogen species peroxynitrite produced during the host immune response. To shed light on the potential mechanism of peroxynitrite detoxification, we have determined the 1.76-Å X-ray crystal structure of LmPP, revealing a striking degree of homology with heme peroxidases. The most outstanding structural feature is a Cys/His heme coordination, which corroborates previous spectroscopic and mutagenesis studies. We also used a combination of stopped-flow and electron paramagnetic spectroscopies that together suggest that peroxynitrite is not a substrate for LmPP catalysis, leaving the function of LmPP an open question.

Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase.

Nitric oxide generated by bacterial nitric oxide synthase (NOS) increases the susceptibility of Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis to oxidative stress, including antibiotic-induced oxidative stress. Not surprisingly, NOS inhibitors also improve the effectiveness of antimicrobials. Development of potent and selective bacterial NOS inhibitors is complicated by the high active site sequence and structural conservation shared with the mammalian NOS isoforms. To exploit bacterial NOS for the development of new therapeutics, recognition of alternative NOS surfaces and pharmacophores suitable for drug binding is required. Here, we report on a wide number of inhibitor-bound bacterial NOS crystal structures to identify several compounds that interact with surfaces unique to the bacterial NOS. Although binding studies indicate that these inhibitors weakly interact with the NOS active site, many of the inhibitors reported here provide a revised structural framework for the development of new antimicrobials that target bacterial NOS. In addition, mutagenesis studies reveal several key residues that unlock access to bacterial NOS surfaces that could provide the selectivity required to develop potent bacterial NOS inhibitors.

Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.

Bacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme.