Pain hypersensitivity, sensorimotor impairment, and decreased muscle force in a novel rat model of radiation-induced peripheral neuropathy.

INTRODUCTION: Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation-induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. METHODS: Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham-radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain-related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. RESULTS: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. CONCLUSIONS: A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation-induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition.

A Modified 270 Degree Closure Technique to Address the Prominent or Locked-Out Premaxilla in Bilateral Cleft Palate Repair.

SUMMARY: The bilateral cleft deformity with a prominent or 'locked-out' premaxilla presents one of the most challenging repairs in cleft surgery. Despite its relative frequency, traditional hard palate repair techniques fail to fully address this deformity and expose surgeons to the risk of development of a large anterior fistula when flaps cannot approximate the premaxilla. This greatly increases morbidity for the patient and creates unnecessary challenges during fistula repair or alveolar cleft bone graft later in childhood. The 270° closure technique extends the nasal closure 270° around the premaxilla, continuing the hard palate repair through the alveolar clefts. This technique has been performed on 41 patients with mean follow up of 10.8 years. The repair was successful in 93% of patients with 3 patients developing palatal fistulae, all posterior to the 270° closure. The 270° cleft palate repair around the prominent premaxilla fills a void in the literature for managing the immense challenge of this deformity. When presurgical orthopedics are not a viable option, this approach can minimize the risk of large or complex fistula formation posterior to the premaxilla.

Optimizing immunofluorescent staining of H vessels within an irradiated fracture callus in paraffin-embedded tissue samples.

H vessels are an essential link in angiogenic-osteogenic coupling and orchestrate the process of bone healing. H vessels are critically deficient in the setting of radiation-induced fractures, which have been reported to occur in up to 25% of patients undergoing radiotherapy. By increasing H-vessel proliferation, Deferoxamine (DFO) revitalizes the physiologic response to skeletal injury and accelerates irradiated fracture repair. H-vessel quantification is therefore an important outcome measure in histologic analysis of bone healing. However, an optimized protocol for staining H vessels in formalin-fixed paraffin-embedded (FFPE) tissue sections has not been reported. With this protocol, we describe a method of staining FFPE bone samples with minimal background fluorescence and high signal-to-noise ratio. We examined mandibular specimens in a rat model of bone healing from a range of fracture conditions, including healthy bone (Fx), irradiated bone (XFx), and irradiated bone with DFO treatment (XFx-DFO). Quantitative analysis revealed a significant increase of H vessels in the XFxDFO group compared to both the Fx and XFx groups. By optimizing immunofluorescent staining of H vessels in FFPE samples across a range of fracture conditions, we offer investigators an efficacious means of producing reliable imaging for quantitative analysis of H vessels in an irradiated fracture callus.

Low Prevalence of Clinically Significant Hyponatremia following Cranial Vault Reconstruction for Single-Suture Craniosynostosis.

BACKGROUND: Patients are commonly monitored for hyponatremia after intracranial procedures, yet the prevalence of hyponatremia after cranial vault reconstruction (CVR) remains unclear. The purpose of this study is to define the prevalence, risk factors, and complications of hyponatremia after CVR to optimize postoperative sodium surveillance protocols. METHODS: Patients with nonsyndromic, single-suture craniosynostosis who underwent primary CVR between 2009 and 2020 at Michigan Medicine were included (n = 231). Demographic, intraoperative, and postoperative characteristics were compared by postoperative hyponatremia status at P < 0.05 significance. Hyponatremia was defined as mild (<135 mEq/L), moderate (<130 mEq/L), or severe (<125 mEq/L) based on the lowest postoperative laboratory draw. RESULTS: Twenty-three patients (10.0%) developed mild postoperative hyponatremia. No patient developed moderate or severe postoperative hyponatremia. On multivariable regression, decreased preoperative sodium level (P = 0.03) and decreased preoperative weight (P = 0.02) were significantly associated with mild postoperative hyponatremia. No patient developed complications or required hospital readmission because of hyponatremia. CONCLUSIONS: This large retrospective cohort study of patients with nonsyndromic single-suture craniosynostosis demonstrated a 10% prevalence of mild, clinically inconsequential hyponatremia and 0% prevalence of moderate or severe, clinically significant hyponatremia after primary CVR. Patients with low preoperative sodium level or weight were at increased risk for developing mild postoperative hyponatremia. The results suggest that patients with preoperative sodium greater than 140 mEq/L or preoperative weight greater than 10 kg may be candidates for limited postoperative sodium surveillance; however, future prospective studies are warranted before implementation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

H Vessel Formation as a Marker for Enhanced Bone Healing in Irradiated Distraction Osteogenesis.

In the setting of bone defects, the injured vasculature and loss of hemodynamic inflow leads to hematoma formation and low oxygen tension which stimulates vascular expansion through the HIf-1α pathway. Most importantly, this pathway upregulates sprouting of type H vessels (CD31hiEmcnhi vessels). H vessels engage in direct interaction with perivascular osteoprogenitor cells (OPCs), osteoblasts, and preosteoclasts of bone formation and remodeling. This angiogenic-osteogenic coupling leads to synchronous propagation of vascular and bony tissue for regenerative healing. A growing body of literature demonstrates that H vessels constitute a large portion of bone's innate capacity for osteogenic healing. We believe that CD31hiEmcnhi vessels play a role in bone healing during distraction osteogenesis (DO). DO is a procedure that utilizes traction forces to facilitate induction of endogenous bone formation and regeneration of surrounding soft tissues such as skin, muscle, tendon, and neurovascular structures. While the H vessel response to mechanical injury is adequate to facilitate healing in normal healthy tissue, it remains inadequate to overcome the devastation of radiation. We posit that the destruction of CD31hiEmcnhi vessels plays a role in precluding DO's effectiveness in irradiated bone defect healing. We aim, therefore, to recapitulate the normal pathway of bony healing by utilizing the regenerative capacity of H vessels. We hypothesize that using localized application of deferoxamine (DFO) will enhance the H vessel-mediated vasculogenic response to radiation damage and ultimately enable osteogenic healing during DO. This discovery could potentially be exploited by developing translational therapeutics to hopefully accelerate bone formation and shorten the DO consolidation period, thereby potentially expanding DO's utilization in irradiated bone healing. Sprague-Dawley rats were divided into three groups: DO, radiation with DO (xDO), and radiation with DO and DFO implantation (xDODFO). Experimental groups received 35 Gy of radiation. All groups underwent DO. The treatment group received injections into the osteotomy site, every other day, beginning on postoperative day (POD) 4 of DFO. Animals were sacrificed on POD 40. For immunohistochemical analysis, mandibles were dissected and fixed in 4% paraformaldehyde for 48 hours, decalcified in Cal-Ex II for 2 days, dehydrated through graded ethanol of increasing concentration, and then embedded in paraffin. Samples were cut into 7-µm thick longitudinally oriented sections including the metaphysis and diaphysis. CD31 and Emcn double immunofluorescent staining were performed to evaluate the extent of CD31hiEmcnhi vessel formation. Bone sections were then stained with conjugated antibodies overnight at 4°C. Nuclei were stained with Hoechst. Slides were also double stained with Osterix and CD31 to study the quantity of H vessel-mediated recruitment of OPCs to accelerate bone healing. Images were acquired with a Nikon Ti2 widefield microscope and analyzed in NIS- Elements Advanced Research 5.41.02 software. The abundance of type H vessels is represented by the area fraction of CD31 + Emcn+ vessel area inside the regenerate sample. OPC concomitant proliferation into the distraction gap is represented by the area fraction of Osterix+ cell area inside of the regenerate sample. There were 6× more type H vessels in DO groups than in xDO groups. Localized DFO significantly increased the abundance of type H vessels of irradiated DO animals compared to xDO by 15× ( p = 0.00133531). Moreover, the DO and xDODFO groups with higher abundance of type H vessels also demonstrated better angiogenesis and osteogenesis outcomes. Interestingly, xDODFO groups doubled the quantity of H vessel formation compared to DO, indicating a supraphysiologic response ( p = 0.044655055). Furthermore, H vessel-mediated recruitment of OPCs mimicked the described H vessel formation trend in our study groups. Irradiated DO groups contained 3× less OPCs compared to DO controls. DFO treatment to xDO animals remediated irradiation damage by containing 12× Osterix+ cells. Finally, DFO treatment of irradiated animals quadrupled osteoprogenitor recruitment into the distraction gap compared to DO controls. In this study, we developed a novel approach to visualize CD31hiEmcnhi in paraffin sections to study DO regeneration. Normal DO demonstrated a significant upregulation of H vessel formation and associated angiogenic-osteogenic coupling. Radiation severely decreased H vessel formation along with an associated significant diminution of new bone formation and nonunion. DFO administration, however, resulted in vascular replenishment and the restoration of high quantities of CD31hiEmcnhi and OPCs, recapitulating the normal process of bony regeneration and repair. DFO treatment remediated new bone formation and bony union in irradiated fields associated with increased H vessel angiogenic-osteogenic coupling. While further studies are required to optimize this approach, the results of this study are incredibly promising for the long-awaited translation of localized DFO into the clinical arena.

"Longitudinal Experience Using Pedicled Buccal Fat Pad Flaps in Cleft Palatoplasty: Mitigating Velopharyngeal Insufficiency Risk and Severity".

BACKGROUND: Cleft palatoplasty commonly results in denuded maxillary bone in the lateral gutter(s) and a posterior void between oral and nasal closures. Bony exposure of the anterior palate subjects the maxilla to scarring and growth restriction, while scar contracture of the posterior void may result in velopharyngeal insufficiency (VPI) and fistula formation. Utilization of the buccal fat pad flap (BFPF) at the time of palatoplasty provides vascularized tissue over these critical areas, thereby reducing the rate of secondary surgery for speech and fistula revision. METHODS: A single-center, retrospective review identified patients who underwent palatoplasty with or without BFPF between 1995-2015. Data collected included cleft type, surgical technique, follow-up duration, and complications. Outcomes included rate of speech surgery and palatal fistula development. Veau phenotype index was computed on a scale of 2-4 as a weighted mean to reflect the frequency of cleft type (Veau II-IV) in BFPF and non-BFPF groups. RESULTS: Charts of 866 patients were reviewed; 212 met inclusion criteria. Of these, 101 received a BFPF. Mean follow-up duration was 11.4 years. Despite a selection bias for more severe clefts, the BFPF group had lower incidence of speech surgery (9.9% vs. 36.9%, p=0.0072). The BFPF group had more mild cases treatable with fat injection (7.9% vs. 2.7%, p=0.0346) and developed fewer fistulas (6.9% vs. 18.0%, p=0.0280). CONCLUSION: Despite the presence of more severe clefts, the BFPF group had a significantly lower rate of speech surgery. The BFPF is a valuable adjunct in primary palatoplasty, reducing VPI and fistula formation.

Reasons for Removal of Rigid Internal Fixation Devices in Craniofacial Surgery: A 20-year Update.

The hardware utilized for rigid internal fixation of the craniofacial skeleton has evolved over time. Thus, the reasons for the unplanned removal of hardware continue to change. The purpose of this study is to compare past (1989-1995) and present (2000-2020) patient cohorts to establish trends related to unplanned removal of craniofacial hardware. A retrospective review study was designed. Data from our institution's original publication describing the unplanned removal of craniofacial hardware (1989-1995) was obtained. Data related to patients who underwent unplanned removal of hardware from 2000 to 2020 was collected from the electronic medical record. A descriptive statistical analysis was performed to compare demographics, reasons for hardware placement, and reasons for unplanned hardware removal between cohorts. This study includes 55 patients treated from 1989 to 1995 and 184 patients treated from 2000 to 2020. The average age at hardware placement decreased from 32 years (1989-1995) to 28 years (2000-2020). The most common reason for hardware placement changed from motor vehicle accident (1989-1995) to congenital deformity (2000-2020). The length of time with hardware in situ increased from 13 months (1989-1995) to 25 months (2000-2020). The most common reason for hardware removal changed from prominent hardware (1989-1995) to hardware exposure (2000-2020). In summary, patients who underwent rigid internal fixation of the craniofacial skeleton from 2000 to 2020 retained their hardware 2 times longer than patients treated from 1989 to 1995. Factors potentially contributing to increased retention include improved surgical technique, decreased profile of hardware, and increased surgeon experience. Further studies are warranted to define preoperative risk factors for unplanned hardware removal.

Adipose-Derived Stem Cells Enhance Graft Incorporation and Mineralization in a Murine Model of Irradiated Mandibular Nonvascularized Bone Grafting.

BACKGROUND: Nonvascularized bone grafting represents a practical method of mandibular reconstruction. However, the destructive effects of radiotherapy on native bone preclude the use of nonvascularized bone grafts in head and neck cancer patients. Adipose-derived stem cells have been shown to enhance bone healing and regeneration in numerous experimental models. The purpose of this study was to determine the impact of adipose-derived stem cells on nonvascularized bone graft incorporation in a murine model of irradiated mandibular reconstruction. METHODS: Thirty isogenic rats were randomly divided into 3 groups: nonvascularized bone graft (control), radiation with nonvascularized bone graft (XRT), and radiation with nonvascularized bone graft and adipose-derived stem cells (ASC). Excluding the control group, all rats received a human-equivalent dose of radiation. All groups underwent mandibular reconstruction of a critical-sized defect with a nonvascularized bone graft from the contralateral hemimandible. After a 60-day recovery period, graft incorporation and bone mineralization were compared between groups. RESULTS: Compared with the control group, the XRT group demonstrated significantly decreased graft incorporation (P = 0.011), bone mineral density (P = 0.005), and bone volume fraction (P = 0.001). Compared with the XRT group, the ASC group achieved a significantly increased graft incorporation (P = 0.006), bone mineral density (P = 0.005), and bone volume fraction (P = 0.013). No significant differences were identified between the control and ASC groups. CONCLUSIONS: Adipose-derived stem cells enhance nonvascularized bone graft incorporation in the setting of human-equivalent radiation.

Longitudinal Assessment of Neurodevelopment in Patients With Nonsyndromic Single-Suture Craniosynostosis: A Retrospective Review of 66 Patients.

The neurodevelopmental consequences of nonsyndromic single-suture (NSS) craniosynostosis are the subject of continued debate. Although the predictive validity of the Bayley Scales of Infant and Toddler Development (Third Edition) (BSID-III) have been questioned, this neurodevelopmental testing battery continues to be widely utilized among multidisciplinary craniofacial teams. The purpose of this study is to evaluate the neurodevelopmental functioning of patients with NSS craniosynostosis before and after surgical correction and the impact of surgical correction on neurodevelopmental trajectory based on BSID-III testing. All patients with NSS craniosynostosis who underwent cranial vault remodeling between 2009 and 2020 were considered for inclusion. Patients who failed to complete BSID-III testing within 2 months of surgery preoperatively and 2 years of surgery postoperatively were excluded. A total of 66 patients met criteria for the study. On language testing, both the preoperative mean score ( P =0.007) and postoperative mean score ( P =0.003) were significantly lower than the population norm. Furthermore, on motor testing, both the preoperative mean score ( P =0.005) and postoperative mean score ( P =0.001) were significantly lower than the population norm. Bayley Scales of Infant and Toddler Development (Third Edition) testing revealed no significant change between preoperative and postoperative neurodevelopmental functioning. Overall, this study suggests that patients with NSS craniosynostosis experience modest delays in language and motor development, which are present before and after cranial vault remodeling. In addition, this study provides evidence that cranial vault remodeling does not significantly impact the neurodevelopmental trajectory. Multicenter st udies and refined neurodevelopmental testing methods are necessary to definitively establish the neurodevelopmental implications of NSS craniosynostosis.

Surgical Timing and Neurocognitive Development among Patients with Craniosynostosis: Analysis of Confounders.

BACKGROUND: In 1988, Renier and Marchac asserted that children with craniosynostosis who undergo cranial vault remodeling (CVR) after 12 months of age experience delayed neurocognitive development compared to children who undergo CVR before 12 months of age. The purpose of this study was to identify factors potentially confounding this cause-and-effect relationship. The authors hypothesize that children with socioeconomic disadvantages or comorbid conditions are more likely to undergo CVR after 12 months and may represent a selection bias toward delayed neurocognitive development. METHODS: Patients with nonsyndromic single-suture craniosynostosis who underwent CVR between 2009 and 2020 at Michigan Medicine were included ( n = 227). Sociodemographic and clinical variables were documented. The sample was dichotomized to compare patients who underwent CVR before (early) and after (late) 12 months of age. Statistical analysis was performed at P < 0.05 significance. RESULTS: The early and late groups contained 157 patients and 70 patients, respectively. Compared to the early group, the late group contained a larger proportion of patients who identified as non-White ( P = 0.03), qualified for need-based financial assistance ( P = 0.03), were born preterm ( P < 0.01), or had a comorbid condition ( P < 0.01). Based on preoperative testing, the late group contained a larger proportion of patients with baseline cognitive ( P < 0.001) and language ( P = 0.008) delays relative to the early group. CONCLUSIONS: This study demonstrates that socioeconomic disadvantages and comorbid conditions are prevalent among patients who undergo delayed CVR and may represent a selection bias toward delayed neurocognitive development. Future studies evaluating the relationship between surgical timing and neurocognitive development must control for these factors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Therapeutic Efficacy of Adipose-Derived Stem Cells Versus Bone Marrow Stromal Cells for Irradiated Mandibular Fracture Repair.

BACKGROUND: Mesenchymal stem cells have immense potential in applications of bone healing and regeneration. However, few studies have evaluated the therapeutic efficacy of adipose-derived stem cells (ASCs) and bone marrow stromal cells (BMSCs) in irradiated bone. The purpose of this study is to compare the ability of ASCs versus BMSCs to enhance healing outcomes in a murine model of irradiated mandibular fracture repair. METHODS: Forty-eight isogenic male Lewis rats underwent radiation therapy followed by mandibular osteotomy with intraoperative placement of either ASCs or BMSCs. Animals were killed on postoperative day 40. Mandibles were analyzed for union rate, biomechanical strength, vascularity, and mineralization. Groups were compared at P < 0.05 significance. RESULTS: The ASC and BMSC groups demonstrated 92% and 75% union rates. Compared with the BMSC group, the ASC group demonstrated a trending increase in maximum load ( P = 0.095) on biomechanical strength analysis and a significant increase in vessel number ( P = 0.001), vessel thickness ( P = 0.035), and vessel volume fraction ( P = 0.007) on micro-computed tomography angiography analysis. No significant differences in bone mineralization were identified on micro-computed tomography analysis. CONCLUSION: This study demonstrates the superior therapeutic efficacy of ASCs over BMSCs in irradiated fracture healing as evidenced by union rate, vascular morphometry, and a trend in biomechanical strength. We posit that the robust vascular response induced by ASCs better recapitulates the sequence and synchronicity of physiologic bone healing compared with BMSCs, thereby improving the reliability of irradiated fracture repair.

Institutional Trends in Opioid Prescribing and Utilization after Primary Cleft Lip and Palate Repair.

BACKGROUND: Outpatient prescriptions for postoperative pain play an important role in the opioid epidemic. Prescribing guidelines are an effective target for intervention but require procedure-specific data to be successful. The aim of this study was to examine opioid prescribing patterns and pain control after primary cleft lip and palate repair at a large academic center. METHODS: Children undergoing cleft lip and palate repair from April of 2018 to July of 2019 were included in a prospective cohort study. Data on discharge prescriptions, refills, and emergency room visits were obtained from the medical record. Caregivers were surveyed 7 to 21 days after surgery regarding pain control, opioid use, education exposure, storage, and disposal. Chi-square tests and one-way analysis of variance were used to examine predictors of pain control, opioid consumption, safe storage, and disposal. RESULTS: After screening, 59 children were included in the study. Patients were 55.8 percent male with a median age of 12 months (interquartile range, 5 to 15). Ninety percent of patients received an opioid prescription at discharge with a mean quantity of 10 doses (interquartile range, 5 to 15). Ninety-seven percent of caregivers used adjunct medication. Opioids were given for a median of 3 days (interquartile range, 2 to 6.5). Seventy-six percent of caregivers gave less opioid than prescribed. There was no association between pain control and opioid quantity ( p = 0.68). Twenty-four percent of caregivers used locked storage. Thirty-four percent of respondents with leftover medication reported disposal. CONCLUSIONS: Opioids are often overprescribed after cleft lip and palate repair. Providers should consider limiting prescriptions to a 3-day supply to help reduce the quantity of opioids available in the community.

Impact of sleep-disordered breathing on behavior and quality of life in children aged 2 to 7 years with non-syndromic cleft lip and/or palate.

INTRODUCTION: Children with cleft are at high risk for sleep-disordered breathing (SDB). However, little is known about the impact of SDB in this pediatric population. The aim of this study was to investigate whether SDB play a role in behavior and quality of life (QoL) in young children with cleft. METHODS: Cross-sectional study of 95 children aged 2.0-7.9 years with cleft palate. Parents completed a sleep (Pediatric Sleep questionnaire), a behavior (Conners' Early Childhood scale), and a generic health-related QoL (KINDL questionnaire) assessment. Symptomatic children were referred for a polysomnography (PSG). RESULTS: Overall, 14.7% of children (49.5% boys) screened positive for SDB and 27.4% had a PSG, which identified 84.6% with sleep apnea (apnea-hypopnea index [AHI] ≥1) and 27.2% with AHI ≥5. Positive screening for SDB was associated with elevated T-scores for anxiety and physical symptoms, significant differences in mean T-scores for inattention/hyperactivity (64.2 ± 15.7 vs. 53.9 ± 11.4, p = .02), social functioning/atypical behaviour, social functioning (60.6 ± 11.7 vs. 51.9 ± 7.3, p = .004 and 59.5 ± 10.9 vs. 51.2 ± 8.0, p = .01) and mood (57.5 ± 8.2 vs. 50.7 ± 8.2, p = .03). Lower QoL scores for emotional and family well-being were also reported in children with SDB (80.7 ± 13.4 vs. 90.0 ± 8.7, p = .01, 66.7 ± 15.8 vs. 76.9 ± 11.9, p = .04). Children with AHI ≥5 compared to those with AHI ≥1 and <5 showed significant differences in mean T-score for aggressive behaviour (65.2 ± 12.1 vs. 52.3 ± 11.3, p = .04), defiant temper (62.8 ± 9.2 vs. 51.6 ± 10.2, p = .03) and lower family QoL scores (59.4 ± 15.2 vs. 77.1 ± 9.6, p = .006). CONCLUSIONS: In children with cleft palate the presence of SDB symptoms and moderate/severe sleep apnea was associated with behavioral (internalizing/externalizing) problems and lower family well-being.

Sleep-related movement disorders and growing pains: differences in daytime and bedtime behavior in 2-6 year old children with cleft palate.

BACKGROUND: Behavioural difficulties are common in children with sleep disorders. However, up to now no study has investigated the association between sleep-related movement disorders (SRMD) and behavior in children with craniofacial cleft. The aim of this study was to assess the frequency and impact of SRMD and growing pains in daytime/bedtime behavior in young children with cleft palate. METHODS: Cross-sectional survey study of sleep and behavior in 2.0-6.9 year old children with cleft palate. Parents completed the Pediatric Sleep Questionnaire, which queries reports of periodic limb movements (PLMS), restless leg syndrome (RLS), growing pains, daytime sleepiness, sleep latency/duration, and the Conners' Early Childhood Questionnaire which asks about behavioral difficulties. RESULTS: Among 71 children with cleft palate (52.1% boys) 14.1 % screened positive for PLMS, 8.5% reported RLS and 9.9% growing pains. Children who screened positive for PLMS and RLS were more likely to report sleepiness (PLMS 40% vs. 4.9%, p = 0.001; RLS 33.3% vs. 7.7%, p = 0.04) and long sleep latency (PLMS 80% vs. 32.8%, p = 0.005; RLS 100% vs. 33.8%, p = 0.002) compared to those who did not endorse the respective sleep problems. Children who reported PLMS had a higher T-score for emotional (58.2 ± 7.6 vs. 50.7 ± 8.4, p = 0.01) and somatic symptoms (66.2 ± 15.2 vs. 49.9 ± 9.5, p = 0.0001). Sleepiness was associated to an increased frequency of externalizing, psychiatric and somatic problems. While children with long sleep latency reported more emotional and somatic symptoms, and those with reduced sleep duration more internalizing difficulties. CONCLUSIONS: Parents of young children with cleft palate reported frequently PLMS, RLS and growing pains. Daytime/bedtime behavior varies depending on the presence of SRMD. Sleepiness and sleep variables might play a role on behavioural problems in children with cleft and SRMD symptoms.

Management of Calcified Cephalohematoma of Infancy: The University of Michigan 25-Year Experience.

BACKGROUND: Cephalohematoma of infancy is the result of a subperiosteal blood collection that usually forms during birth-related trauma. A small proportion of cephalohematomas can calcify over time, causing a permanent calvarial deformity that is only correctable with surgery. The authors present a technique for the excision and reconstruction of calcified cephalohematoma and their management experience over the past 25 years. METHODS: All patients with a diagnosis of calcified cephalohematoma between 1994 and 2019 were identified. Patients were included if the diagnosis was confirmed by a pediatric plastic surgeon or a neurosurgeon. All patients underwent surgical evaluation followed by surgical intervention or observation. Patient demographics and potential risk factors for both surgical and nonsurgical groups were compared using chi-square or Fisher's exact test. Additional data were collected for the surgical cohort. RESULTS: Of 160 infants diagnosed with cephalohematoma, 72 met inclusion criteria. Thirty patients underwent surgical treatment. There was no significant difference in demographics, baseline characteristics, or potential risk factors between the operative and nonoperative groups. Mean age at the time of surgery was 8.6 months. Twenty-one surgical patients (70 percent) required inlay bone grafting. All surgery patients had improvement in calvarial shape. The main risk of surgery was blood loss requiring transfusion [eight patients (26.7 percent)]. Thirteen percent of patients experienced minor complications. CONCLUSIONS: This series of 72 children with calcified cephalohematomas, 30 of whom required surgical intervention, is one of the largest to date. The technique presented herein demonstrated excellent surgical outcomes by restoring normal cranial contours and was associated with a low complication profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Combating Constraints of the Functional Matrix: The Importance of Overcorrection in Pediatric Craniofacial Surgery.

BACKGROUND: To effectively manipulate the bone, particularly in the growing patient, the craniofacial surgeon must understand the principles related to bone-based reconstruction. A theory of craniofacial growth that is both biologically accurate and clinically relevant is thus needed. METHODS: A historical review of major findings across various disciplines (including orthopedic surgery, anatomy, embryology, orthodontics, and cell biology) will be covered, as it pertains to the concept of the functional matrix of the craniofacial skeleton. RESULTS: The functional matrix dictates the interplay between the soft tissue envelope and bone grafts, thus guiding donor site choice and inset methods. The soft tissue may also warrant the use of bony hypercorrection especially in cranial vault remodeling. Control of both bone and boundaries of the soft tissue functional matrix can be achieved via distraction osteogenesis. CONCLUSION: The soft tissue functional matrix must be accounted for during craniofacial bone grafting, mobilizing osteotomies, and distraction osteogenesis if optimal aesthetic results are to be obtained using the least amount of procedures.

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields.

BACKGROUND: The incidence of cancer worldwide is expected to be more than 22 million annually by 2030. Approximately half of these patients will likely require radiation therapy. Although radiotherapy has been shown to improve disease control and increase survivorship, it also results in damage to adjacent healthy tissues, including the bone, which can lead to devastating skeletal complications, such as nonunion, pathologic fractures, and osteoradionecrosis. Pathologic fractures and osteoradionecrosis are ominous complications that can result in large bone and soft tissue defects requiring complex reconstruction. Current clinical management strategies for these conditions are suboptimal and dubious at best. The gold standard in treatment of severe radiation injury is free tissue transfer; however, this requires a large operation that is limited to select candidates. METHODS: With the goal to expand current treatment options and to assuage the devastating sequelae of radiation injury on surrounding normal tissue, our laboratory has performed years of translational studies aimed at remediating bone healing and regeneration in irradiated fields. Three therapeutics (amifostine, deferoxamine, and adipose-derived stem cells) have demonstrated great promise in promoting healing and regeneration of irradiated bone. RESULTS: Amifostine confers prophylactic protection, whereas deferoxamine and adipose-derived stem cells function to remediate postradiation associated injury. CONCLUSIONS: These prospective therapeutics exploit a mechanism attributed to increasing angiogenesis and ultimately function to protect or restore cellularity, normal cellular function, osteogenesis, and bone healing to nonirradiated metrics. These discoveries may offer innovative treatment alternatives to free tissue transfer with the added benefit of potentially preventing and treating osteoradionecrosis and pathologic fractures.

Bone Morphogenetic Protein-2 and Demineralized Bone Matrix in Difficult Bony Reconstructions in Cleft Patients.

Reconstruction of alveolar clefts includes fistula repair and bone grafting. However, bone is often harvested from the iliac crest or the skull, which can be associated with considerable donor site morbidity, and the failure rate may be as high as 20%. As such, some centers utilize bone morphogenetic protein (BMP)-2 to reconstruct the bony cleft. However, this remains an off-label use, and therefore we propose using BMP-2 only in patients with tenuous soft tissues, when the likelihood of graft failure is high. In four patients, we used BMP-2 with demineralized bone matrix (DBM) to reconstruct defects related to clefts-three patients had alveolar clefts, and the fourth patient was referred to us, with resorption of a necrotic premaxilla after premaxillary setback. In all cases, the decision was made to forego bone grafting intraoperatively given the poor quality of soft tissue and the increased risk of bone graft exposure. BMP-2 was infused onto a carrier and placed in the fistula, and Grafton DBM was then packed into the defect. In three cases, small amounts of bone from the piriform aperture were mixed with the BMP-2/DBM. After 3-7 months, all patients had generated bone in the clefts and did not require bone grafting. While we continue to prefer a "like with like" reconstruction, bone grafting has a high likelihood of failure in patients with suboptimal soft tissues or tight closures. We suggest that combining BMP-2 and DBM in higher risk patients is an excellent option to avoid bone graft loss and reoperation.