Optimal Dosing of Levetiracetam for Seizure Prophylaxis in Critically Ill Patients: A Prospective Observational Study.

OBJECTIVES: Critically ill patients eliminate levetiracetam (LEV) more rapidly than healthy controls, yet low doses are commonly used for seizure prophylaxis in the ICU setting. We compared the rates of achievement of target serum levels and new onset seizure (clinical and/or electrographic) among patients who received low (500 mg bid) versus high (750-1,000 mg bid) dose LEV. DESIGN: Prospective, observational study. SETTING: Tertiary care, academic center. PATIENTS: We included patients who received prophylactic LEV following traumatic brain injury, intracerebral hemorrhage, spontaneous subarachnoid hemorrhage, or supratentorial neurosurgery between 2019 and 2021. Patients with a history of seizure, antiseizure medication use, or renal failure requiring dialysis were excluded. INTERVENTIONS: None. MEASUREMENTS: LEV levels were obtained at steady state. The impact of low-dose versus high-dose LEV on the primary outcome of target LEV levels (12-46 µg/mL), and the secondary outcome of clinical and/or electrographic seizure, were assessed using multivariable logistic regression analyses adjusting for age, LEV loading dose, BMI, primary diagnosis and creatinine clearance (CrCl). MAIN RESULTS: Of the 205 subjects included in analyses, n = 106 (52%) received LEV 500 mg bid (median 13 mg/kg/d), and n = 99 (48%) received LEV 750-1,000 mg bid (median 25 mg/kg/d). Overall, 111 of 205 patients (54%) achieved target levels: 48 (45%) from the low-dose group versus 63 (64%) from the high-dose group (odds ratio [OR] 2.1; 95% CI, 1.1-3.7; p = 0.009). In multivariable analyses, high-dose LEV predicted target levels (adjusted OR [aOR] 2.23; 95% CI, 1.16-4.27; p = 0.016), and was associated with lower seizure odds (aOR 0.32; 95% CI, 0.13-0.82; p = 0.018) after adjusting for age, loading dose, BMI, diagnosis, and CrCl. CONCLUSIONS: Underdosing of LEV was common, with only 54% of patients achieving target serum levels. Higher doses (750-1,000 mg bid) were more than twice as likely to lead to optimal drug levels and reduced the odds of seizure by 68% compared with low-dose regimens (500 mg bid).

Poor Accuracy of Manually Derived Head Computed Tomography Parameters in Predicting Intracranial Hypertension After Nontraumatic Intracranial Hemorrhage.

BACKGROUND: The utility of head computed tomography (CT) in predicting elevated intracranial pressure (ICP) is known to be limited in traumatic brain injury; however, few data exist in patients with spontaneous intracranial hemorrhage. METHODS: We conducted a retrospective review of prospectively collected data in patients with nontraumatic intracranial hemorrhage (subarachnoid hemorrhage [SAH] or intraparenchymal hemorrhage [IPH]) who underwent external ventricular drain (EVD) placement. Head CT scans performed immediately prior to EVD placement were quantitatively reviewed for features suggestive of elevated ICP, including temporal horn diameter, bicaudate index, basal cistern effacement, midline shift, and global cerebral edema. The modified Fisher score (mFS), intraventricular hemorrhage score, and IPH volume were also measured, as applicable. We calculated the accuracy, positive predictive value (PPV), and negative predictive value (NPV) of these radiographic features for the coprimary outcomes of elevated ICP (> 20 mm Hg) at the time of EVD placement and at any time during the hospital stay. Multivariable backward stepwise logistic regression analysis was performed to identify significant radiographic factors associated with elevated ICP. RESULTS: Of 608 patients with intracranial hemorrhages enrolled during the study time frame, 243 (40%) received an EVD and 165 (n = 107 SAH, n = 58 IPH) had a preplacement head CT scan available for rating. Elevated opening pressure and elevated ICP during hospitalization were recorded in 48 of 152 (29%) and 103 of 165 (62%), respectively. The presence of ≥ 1 radiographic feature had only 32% accuracy for identifying elevated opening pressure (PPV 30%, NPV 58%, area under the curve [AUC] 0.537, 95% asymptotic confidence interval [CI] 0.436-0.637, P = 0.466) and 59% accuracy for predicting elevated ICP during hospitalization (PPV 63%, NPV 40%, AUC 0.514, 95% asymptotic CI 0.391-0.638, P = 0.820). There was no significant association between the number of radiographic features and ICP elevation. Head CT scans without any features suggestive of elevated ICP occurred in 25 of 165 (15%) patients. However, 10 of 25 (40%) of these patients had elevated opening pressure, and 15 of 25 (60%) had elevated ICP during their hospital stay. In multivariable models, mFS (adjusted odds ratio [aOR] 1.36, 95% CI 1.10-1.68) and global cerebral edema (aOR 2.93, 95% CI 1.27-6.75) were significantly associated with elevated ICP; however, their accuracies were only 69% and 60%, respectively. All other individual radiographic features had accuracies between 38 and 58% for identifying intracranial hypertension. CONCLUSIONS: More than 50% of patients with spontaneous intracranial hemorrhage without radiographic features suggestive of elevated ICP actually had ICP > 20 mm Hg during EVD placement or their hospital stay. Morphological head CT findings were only 32% and 59% accurate in identifying elevated opening pressure and ICP elevation during hospitalization, respectively.

Levetiracetam for Seizure Prophylaxis in Neurocritical Care: A Systematic Review and Meta-analysis.

BACKGROUND: Levetiracetam is commonly used for seizure prophylaxis in patients with intracerebral hemorrhage (ICH), traumatic brain injury (TBI), supratentorial neurosurgery, and spontaneous subarachnoid hemorrhage (SAH). However, its efficacy, optimal dosing, and the adverse events associated with levetiracetam prophylaxis remain unclear. METHODS: A systematic search of PubMed, Embase, and Cochrane central register of controlled trials (CENTRAL) database was conducted from January 1, 2000, to October 30, 2020, including articles addressing treatment with levetiracetam for seizure prophylaxis after SAH, ICH, TBI, and supratentorial neurosurgery. Non-English, pediatric (aged < 18 years), preclinical, reviews, case reports, and articles that included patients with a preexisting seizure condition or epilepsy were excluded. The coprimary meta-analyses examined first seizure events in (1) levetiracetam versus no antiseizure medication and (2) levetiracetam versus other antiseizure medications in all ICH, TBI, SAH, and supratentorial neurosurgery populations. Secondary meta-analyses evaluated the same comparator groups in individual disease populations. Risk of bias in non-randomised studies - of interventions (ROBINS-I) and risk-of-bias tool for randomized trials (RoB-2) tools were used to assess risk of bias. RESULTS: A total of 30 studies (n = 6 randomized trials, n = 9 prospective studies, and n = 15 retrospective studies), including 7609 patients (n = 4737 with TBI, n = 701 with SAH, n = 261 with ICH, and n = 1910 with neurosurgical diseases) were included in analyses. Twenty-seven of 30 (90%) studies demonstrated moderate to severe risk of bias, and 11 of 30 (37%) studies used low-dosage levetiracetam (250-500 mg twice daily). In the primary meta-analyses, there were no differences in seizure events for levetiracetam prophylaxis (n = 906) versus no antiseizure medication (n = 2728; odds ratio [OR] 0.79, 95% confidence interval [CI] 0.53-1.16, P = 0.23, fixed-effect, I2 = 26%, P = 0.23 for heterogeneity) or levetiracetam (n = 1950) versus other antiseizure prophylaxis (n = 2289; OR 0.84, 95% CI 0.55-1.28, P = 0.41, random-effects, I2 = 49%, P = 0.005 for heterogeneity). Only patients with supratentorial neurosurgical diseases benefited from levetiracetam compared with other antiseizure medications (median 0.70 seizure events per-patient-year with levetiracetam versus 2.20 seizure events per-patient-year for other antiseizure medications, OR 0.34, 95% CI 0.20-0.58, P < 0.001, fixed-effects, I2 = 39%, P = 0.13 for heterogeneity). There were no significant differences in meta-analyses of patients with ICH, SAH, or TBI. Adverse events of any severity were reported in a median of 8% of patients given levetiracetam compared with 21% of patients in comparator groups. CONCLUSIONS: Based on the current moderately to seriously biased heterogeneous data, which frequently used low and possibly subtherapeutic doses of levetiracetam, our meta-analyses did not demonstrate significant reductions in seizure incidence and neither supports nor refutes the use of levetiracetam prophylaxis in TBI, SAH, or ICH. Levetiracetam may be preferred post supratentorial neurosurgery. More high-quality randomized trials of prophylactic levetiracetam are warranted.

Toxic Metabolic Encephalopathy in Hospitalized Patients with COVID-19.

BACKGROUND: Toxic metabolic encephalopathy (TME) has been reported in 7-31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. METHODS: We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase-polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020. TME was diagnosed in patients with altered mental status off sedation or after an adequate sedation washout. Patients with structural brain disease, seizures, or primary neurological diagnoses were excluded. The coprimary outcomes were the prevalence of TME stratified by etiology and in-hospital mortality (excluding comfort care only patients) assessed by using a multivariable time-dependent Cox proportional hazards models with adjustment for age, race, sex, intubation, intensive care unit requirement, Sequential Organ Failure Assessment scores, hospital location, and date of admission. RESULTS: Among 4491 patients with COVID-19, 559 (12%) were diagnosed with TME, of whom 435 of 559 (78%) developed encephalopathy immediately prior to hospital admission. The most common etiologies were septic encephalopathy (n = 247 of 559 [62%]), hypoxic-ischemic encephalopathy (HIE) (n = 331 of 559 [59%]), and uremia (n = 156 of 559 [28%]). Multiple etiologies were present in 435 (78%) patients. Compared with those without TME (n = 3932), patients with TME were older (76 vs. 62 years), had dementia (27% vs. 3%) or psychiatric history (20% vs. 10%), were more often intubated (37% vs. 20%), had a longer hospital length of stay (7.9 vs. 6.0 days), and were less often discharged home (25% vs. 66% [all P < 0.001]). Excluding comfort care patients (n = 267 of 4491 [6%]) and after adjustment for confounders, TME remained associated with increased risk of in-hospital death (n = 128 of 425 [30%] patients with TME died, compared with n = 600 of 3799 [16%] patients without TME; adjusted hazard ratio [aHR] 1.24, 95% confidence interval [CI] 1.02-1.52, P = 0.031), and TME due to hypoxemia conferred the highest risk (n = 97 of 233 [42%] patients with HIE died, compared with n = 631 of 3991 [16%] patients without HIE; aHR 1.56, 95% CI 1.21-2.00, P = 0.001). CONCLUSIONS: TME occurred in one in eight hospitalized patients with COVID-19, was typically multifactorial, and was most often due to hypoxemia, sepsis, and uremia. After we adjustment for confounding factors, TME was associated with a 24% increased risk of in-hospital mortality.

Role of the brain melanocortins in blood pressure regulation.

Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)-MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, and urinary catecholamine excretion, as well as attenuated SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.

Obesity-Induced Hypertension: Brain Signaling Pathways.

Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.

The Effect of Activated Protein C on Attenuation of Ischemia-Reperfusion Injury in a Rat Muscle Flap Model.

Ischemia-reperfusion injury is often the final and irreversible factor causing flap failure in microsurgery. The salvage of a microsurgical flap with an ischemia-reperfusion injury contributes to the success of microsurgical flap transfers. Activated protein C (APC), a serine protease with anticoagulant and anti-inflammatory activities, has been shown to improve ischemic flap survival. To date, APC has yet to be applied to models of free flap with ischemia-reperfusion injury. In this study, we aimed to investigate the effect of APC on gracilis flap ischemia-reperfusion injury induced by gracilis vessels clamping and reopening. Sixty male Sprague-Dawley rats were randomly divided into 2 groups. After 4 hours of clamping for ischemia, flaps were reperfused and recombinant human APC (25 µg/kg) or saline was injected in the flaps through pedicles. At 0, 1, 4, 18, and 24 hours after injection (n = 6 for each time point), the tissue samples were harvested. The muscle viability at 24 hours in saline group was 54.8% (15.1%), whereas the APC-treated group was 90.0% (4.3%) (P < 0.05). The induced nitric oxide synthase (iNOS) mRNA expression increased with the time after reperfusion, which were 0.93 (0.25) to 2.09 (0.22) in saline group, and 0.197 (0.15) to 0.711 (0.15) in the APC-treated group. iNOS mRNA expression in the APC-treated group was significantly higher than the saline group at 1, 18, and 24 hours (P < 0.05). Numerous inflammatory cells were observed infiltrating and invading the muscle fibers in the saline group more than the APC-treated group. Increased number of polymorphonuclear cells was also noted in the saline group compared with the APC-treated group (P < 0.05). In conclusion, APC treatment can significantly attenuate ischemia-reperfusion injury and increase the survival of the free flap through down-regulating iNOS mRNA expression and reducing the inflammatory cells. Further research is still needed to be done on various mechanisms in which APC is protective to prevent tissue damage.

Comparison of Plastic Surgery Residency Training in United States and China.

BACKGROUND: Residency training is internationally recognized as the only way for the physicians to be qualified to practice independently. China has instituted a new residency training program for the specialty of plastic surgery. Meanwhile, plastic surgery residency training programs in the United States are presently in a transition because of restricted work hours. The purpose of this study is to compare the current characteristics of plastic surgery residency training in 2 countries. METHODS: Flow path, structure, curriculum, operative experience, research, and evaluation of training in 2 countries were measured. The number of required cases was compared quantitatively whereas other aspects were compared qualitatively. RESULTS: Plastic surgery residency training programs in 2 countries differ regarding specific characteristics. Requirements to become a plastic surgery resident in the United States are more rigorous. Ownership structure of the regulatory agency for residency training in 2 countries is diverse. Training duration in the United States is more flexible. Clinical and research training is more practical and the method of evaluation of residency training is more reasonable in the United States. The job opportunities after residency differ substantially between 2 countries. Not every resident has a chance to be an independent surgeon and would require much more training time in China than it does in the United States. CONCLUSIONS: Plastic surgery residency training programs in the United States and China have their unique characteristics. The training programs in the United States are more standardized. Both the United States and China may complement each other to create training programs that will ultimately provide high-quality care for all people.

Clinical application of cultured epithelial autografts on acellular dermal matrices in the treatment of extended burn injuries.

Achieving permanent replacement of skin in extensive full-thickness and deep partial-thickness burn injuries and chronic wounds remains one of the fundamental surgical problems. Presently, split-thickness skin grafts are still considered the best material for surgical repair of an excised burn wound. However, in burns that affect greater than 50% of total body surface area, the patient has insufficient areas of unaffected skin from which split-thickness skin grafts can be harvested. The use of cultured epithelial (or epidermal) autografts (CEAs) has achieved satisfactory results. But the take rate of CEAs is poor in full-thickness bed or in chronically infected area. Providing temporary cover with allograft skin, or a more permanent allodermis, may increase clinical take. This review aims to (1) describe the use of CEAs in the regeneration of the epidermis, (2) introduce the application of the acellular dermal matrices (ADMs) in the clinics, and (3) enhance understanding of the CEAs applied with ADM as an appropriate strategy to treat the extended burn injuries. The current evidence regarding the cultured epithelial cell or keratinocyte autograft and dermal grafts applied in the treatment of burn injuries was investigated with an extensive electronic and manual search (MEDLINE and EMBASE). The included literature (N=136 publications) was critically evaluated focusing on the efficacy and safety of this technique in improving the healing of the deep dermal and full-thickness burn injuries. This review concluded that the use of ADM with CEAs is becoming increasingly routine, particularly as a life-saving tool after acute thermal trauma.

Changes of the donor nerve in end-to-side neurorrhaphies with epineurial window and partial neurectomy: a long-term evaluation in the rat model.

End-to-side (ETS) neurorrhaphy has been applied in the repair of peripheral nerve injuries and in babysitter procedures. However, the long-term changes of donor nerve and muscle after ETS remain unknown. This study was designed to investigate long-term changes in donor nerve and muscle in a rat model. Sixty Lewis rats were equally allocated into three groups of 20 rats. The peroneal nerve was divided. In Group A, end-to-end (ETE) neurorrhaphy was performed. In Group B, ETS was performed to an epineurial window on the tibial nerve. In Group C, ETS was performed to the tibial nerve with 40% partial neurectomy. The following data were obtained at 6, 12, 18, and 24 weeks postoperatively: latency delaying rate (LDR), amplitude recovery rate (ARR), myelinated fiber counts, muscle force and weight, and cross-sectional area of gastrocnemius muscle fibers. The results showed no significant changes of the donor nerve and muscle in Group B. Nerve regeneration was found in the peroneal nerve, and myelinated fiber number was significantly decreased when compared to the nerve with ETE. In Group C, the myelinated axon number in the peroneal nerve was equivalent to the level in ETE repair. However, function and structure of the donor nerve and muscle were significantly impaired in the early postoperative period. Nonetheless, full recovery was observed 24 weeks after surgery. Both ETS with epineurial window and 40% donor nerve neurectomy showed reinnervation of the recipient nerve without structural and functional changes of the donor system in a long-term follow-up. Partial neurectomy may promote recipient nerve regeneration, but at the cost of donor neuromuscular compromises in the early postoperative period. This study provides long-term evidence for further investigation of ETS in peripheral nerve repair and in babysitter procedures.

Effects of vascular endothelial growth factor on survival of surgical flaps: a review of experimental studies.

Partial or complete necrosis of skin flaps remains a significant problem in plastic and reconstructive surgery. Growth factors have shown promise in improving flap survival through increased angiogenesis and blood supply to the flap. Vascular endothelial growth factor (VEGF) is the most widely investigated and successful one. But the mechanisms of the effects are still not very clear. In the course of a series of experiments, we indicated that tissue survival of surgical flaps could be improved by both preoperative (sustained phase effect) and intraoperative (acute phase effect) application of VEGF. We reviewed both experimental and clinical investigations on the use of VEGF with surgical flaps to summarize the evidence of both phases of VEGF activity in promotion of flaps survival in detail. With the combinations of acute and sustained phases of effects, VEGF protein and gene, VEGF morphologic actions, and VEGF histochemical modulations suggest a pattern of VEGF activity that can be superimposed on classic descriptive mechanisms of tissue survival of flaps.

Recipient vessels in the free flap reconstruction around the knee.

Microsurgical free tissue transfer is playing a critical role in reconstruction of the soft tissue around the knee to salvage the limb, especially when the defects exist with a wide zone of injury or with a poor soft tissue condition, where local flaps are unavailable. For a successful free flap transfer, proper selection of a recipient vessel is essential and challenging. The survival and other outcomes of the transferred flaps were closely related to which recipient vessel was used and the location of anastomosis. In this article, we review most of the clinical reports about using free flaps to reconstruct the soft tissue around the knee, excluding the cases of postamputation, and discuss about the recipient vessels that can be used.

Effect of sildenafil on peripheral nerve regeneration.

In this study, we investigated whether sildenafil, a cyclic guanosine monophosphate-dependent phospodiesterase-5 inhibitor, could promote functional nerve regeneration after surgical section and repair of the sciatic nerve in rats. Nerve regeneration was studied in a rat sciatic nerve transected and repair model. The animals were randomly assigned to one of the following 3 treatment groups (n = 20/group): sildenafil-treated group 1 (5 mg/kg/d subcutaneously, for 7 days), sildenafil-treated group 2 (5 mg/kg/d subcutaneously, for 42 days), and control group given saline solution (once per day subcutaneously). Walking track analysis, electromyography, and histological evaluation were performed on day 90 after repair operation. The results showed that the sciatic functional index of sildenafil-treated group 1 (data) was slightly better than that of sildenafil-treated group 2 (data) and control group (data) on postoperative day 90. However, the difference was not statistically significant (P = 0.073). No significant differences of the motor nerve conduction velocity were found between experimental groups [18 (2.4) and 20 (4.1 m/s)] and saline control group [19.5 (3.0) m/s] (P = 0.68). Comparison of myelinated axon count of regenerated nerve of the rat between the sildenafil-treated group 1, sildenafil-treated group 2, and saline group was also not significantly different (P = 0.56). In conclusion, administration of sildenafil after nerve repair surgery was found to have positive but insignificant effects on several parameters of nerve regeneration. Further studies could clarify this trend suggesting enhanced nerve regeneration mediated by sildenafil.

Free deep inferior epigastric artery perforator flap for reconstruction of soft-tissue defects in extremities of children.

The deep inferior epigastric artery perforator (DIEP) flap has been a valuable tool in breast reconstruction, but seldom in extremity reconstruction. The aim of this report is to present our experience on the use of the DIEP flap for reconstruction of soft-tissue defects in the extremities of pediatric patients. From January 2007 to February 2011, 22 consecutive free DIEP flap transfers were performed for reconstruction of complex soft-tissue defects in the extremities of children with a mean age of 5.7 years old (ranging 2-10 years old). The flap design included transverse, oblique, and irregular DIEP flaps, containing one to three perforators in the flap. The flap size ranged from 7 × 4 cm to 18 × 17 cm. Primary donor-site closure was accomplished in all of patients. The postoperative course was uneventfully in most of cases. The venous congestion was observed in two cases. One case of venous congestion was caused by flap inset with tension. The other case with venous thrombosis ended with partial loss of the flap after salvage procedure. There was one total flap loss due to the arterial thrombosis. The flap survival rate was 95.5%. The mean follow-up was 12 months (ranging 6-36 months). All reconstructed extremities had satisfactory aesthetic and functional outcomes except two cases undergoing the secondary debulking procedures. The donor sites healed well in all cases without complications. Our experience showed that the free DIEP flap could be an alternative for reconstruction of soft-tissue defects in the extremities of children.

Vascularized fibular grafts in patients with avascular necrosis of femoral head: a systematic review and meta-analysis.

BACKGROUND: Vascularized fibular grafting (VFG) has been initiated to treat avascular necrosis of the femoral head (ANFH) since the late 1970s. There are a number of review articles updating the use of VFG to treat the ANFH. None of them applied statistical analysis for combining results from different studies to obtain a quantitative estimate of the overall effect and potential harm of VFG in comparison to other treatment. METHODS: Several electronic databases were searched to find studies using VFG to treat ANFH. The outcomes sought included Harris Score, failure rate (conversion to total hip arthroplasty (THA) and/or femoral head collapse), and complications rate. Included studies were assessed for methodological bias and estimates of effect were calculated. Potential reasons for heterogeneity were explored. RESULTS: The clinical results of 69.0 % of VFG-treated patients and 25.0 % of non-VFG-treated patients were good to excellent (OR 0.13; p < 0.01). The conversion rate to THA of VFG-treated and that of other methods treated hips was 16.5 % and 42.6 % (OR 0.19; p < 0.001). Collapse rate of VFG-treated and that of non-VFG-treated hips was 16.7 % and 63.6 % (OR 0.09; p < 0.05). The complication rate of VFG-treated and that of other methods treated patients was 23.8 % and 8.9 % (OR 3.44; p = 0.09). For Steinberg stage I, II ANFH, failure rate of VFG-treated and that of non-VFG-treated hips was 9.8 % and 40.2 % (OR 0.17; p < 0.001). For Steinberg stage II, III ANFH, failure rate of VFG-treated and that of non-VFG-treated hips was 16.5 % and 42.8 %, respectively (OR 0.17; p < 0.001). CONCLUSIONS: VFG is a justified method that can prevent the ANFH from progressing to collapse, and that can retard or avoid hip replacement, especially in the hips of Steinberg stage I, II, and III.

Vancomycin-loaded nano-hydroxyapatite pellets to treat MRSA-induced chronic osteomyelitis with bone defect in rabbits.

OBJECTIVE: To investigate nano-hydroxyapatite (nHA) pellets as carriers for vancomycin in the treatment of chronic osteomyelitis and bone defects due to methicillin-resistant Staphylococcus aureus (MRSA) strains. METHODS: Chronic osteomyelitis was induced in 45 New Zealand white rabbits. After 3 weeks (chronic infection), all animals were treated with debridement. The rabbits were divided into an experimental group (the bone was filled with vancomycin-loaded nHA pellets), a control group (the bone was filled with nHA pellets alone), and a blank group. The drug release profiles were determined in vitro and in vivo. X-rays, bone specimens, and microorganism cultures were used to evaluate the efficacy of the treatments. RESULTS: Following a rapid initial release into the circulation, the drug concentration remained effective in the osseous and soft tissues for 12 weeks after debridement. Within 3 months, all rabbits in the experimental group recovered from osteomyelitis without a recurrence of the infection and the bone defects were partially repaired, whereas the infection and bone defects persisted in the control and blank groups. CONCLUSIONS: The results demonstrate that vancomycin-loaded nHA pellets successfully repair bone defects and control infection in MRSA-induced chronic osteomyelitis. In addition, nHA is an effective and safe controlled-release vancomycin carrier for chronic osteomyelitis with bone defects that is induced by MRSA.

Comparison Between Clinically Available Low-Intensity Pulsed Ultrasound (LIPUS) and a Novel Bimodal Acoustic Signal System for Accelerating Fracture Healing.

Low-intensity pulsed ultrasound (LIPUS) accelerates fracture healing by stimulating the production of bone callus and the mineralization process. This study compared a novel bimodal acoustic signal (BMAS) device for bone fracture healing to a clinical LIPUS system (EXOGEN; Bioventus, Durham, NC, USA). Thirty rabbits underwent a bilateral fibular osteotomy. Each rabbits' legs were randomized to receive 20-min treatment daily for 18 days with BMAS or LIPUS. The latter utilizes a longitudinal ultrasonic mode only, while the former employs ultrasound-induced shear stress to promote bone formation. Power Doppler imaging (PDI) was acquired days 0, 2, 4, 7, 11, 14, and 18 post-surgery to monitor treatment response and quantified off-line. X-rays were acquired to evaluate fractures on days 0, 14, 18, and 21. Seventeen rabbits completed the study and were euthanized day 21 post-surgery. The fibulae were analyzed to determine maximum torque, initial torsional stiffness, and angular displacement at failure. ANOVAs and paired t-tests were used to compare pair-wise outcome variables for the two treatment modes on a per rabbit basis. The BMAS system induced better fracture healing with greater stiffness (BMAS 0.21 ± 0.19 versus LIPUS 0.16 ± 0.19 [Formula: see text]cm/°, p = 0.050 ) and maximum torque (BMAS 7.84 ± 5.55 versus LIPUS 6.26 ± 3.46 [Formula: see text]cm, p = 0.022 ) than the LIPUS system. Quantitative PDI assessments showed a higher amount of vascularity with LIPUS than BMAS on days 4 and 18 ( ). In conclusion, the novel BMAS technique achieved better bone fracture healing response than the current Food and Drug Administration (FDA)-approved LIPUS system.

Do Inflammatory Cytokines Affect Patient Outcomes After ACDF?

STUDY DESIGN: Prospective cohort study. OBJECTIVE: The aim was to determine the relationship between serum inflammatory mediators, preoperative cervical spine disease severity, and clinical outcomes after anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Given the role of the inflammatory cascade in spinal degenerative disease, it has been hypothesized that inflammatory markers may serve as a predictor of patient outcomes after surgery. MATERIALS AND METHODS: All patients over age 18 who underwent ACDF for cervical spondylosis with associated radiculopathy and/or myelopathy between 2015 and 2017 from a single institution were prospectively recruited. Preoperative serum inflammatory markers including interleukin (IL)-6, IL-8, tumor necrosis factor-α, high-mobility group box-1 (HMGB1), and white blood cells were measured and correlated to patient demographics, surgical characteristics, duration of symptoms, previous opioid use, and preoperative and 1-year postoperative patient-reported outcomes measures (PROMs) including the neck disability index (NDI), visual analog scale neck pain, visual analog scale arm pain, and Physical and Mental Component Scores of the Short Form-12 (PCS and MCS, respectively) using spearman's rho coefficient. RESULTS: A total of 77 patients were enrolled with follow-up PROMs available for 62% (n=48) of patients at a minimum of 1-year after ACDF. The absolute concentrations of IL-6 and tumor necrosis factor-α were found to be weakly correlated with one another (ρ=0.479). Preoperative symptoms lasting <1-year were weakly correlated with elevation in HMGB1 (ρ=0.421). All other patient demographics exhibited negligible correlation with the preoperative inflammatory markers. Lower preoperative PCS (ρ=0.355) and higher preoperative NDI (ρ=0.336) were weakly correlated with elevated HMGB1. Lower MCS (ρ=0.395) and higher NDI (ρ=0.317) preoperatively were weakly correlated with elevated white blood cells. Postoperative improvement in MCS (ρ=0.306) and MCS recovery ratio (ρ=0.321) exhibited a weakly positive correlation with IL-6. CONCLUSION: Preoperative cytokine levels demonstrated minimal correlation with preoperative symptoms or clinical improvement, suggesting that profiling of patient cytokines has limited utility in predicting outcomes after ACDF. LEVEL OF EVIDENCE: Level III.

GSK-3ß inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury.

Previous studies have shown that GSK-3ß inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3ß inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3ß inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3ß inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3ß inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury.

Comparison of stand-alone polyetheretherketone cages and iliac crest autografts for the treatment of cervical degenerative disc diseases.

BACKGROUND: Anterior cervical decompression and fusion (ACDF) is a widely accepted surgical procedure for the treatment of cervical degenerative disc diseases. This retrospective study was designed to analyze and compare the efficacy and outcomes of anterior cervical fusion using stand-alone polyetheretherketone (PEEK) cages and autogenous iliac crest grafts with the anterior cervical plating system. METHODS: A total of 72 consecutive patients suffering from cervical degenerative disc diseases treated with ACDF from June 2005 to Dec 2008 were enrolled in the study. Patients in group A (40 patients, 64 segments) had anterior interbody fusion with stand-alone PEEK cages and patients in group B (32 patients, 51 segments) with autogenous iliac crest graft combined with anterior plate fixation. The operative time and intraoperative blood loss were recorded. Clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) scoring system; cervical lordosis, intervertebral height, and cervical fusion status were assessed on X-ray and computed tomography. FINDINGS: The mean follow-up period was 17.3 months in the stand-alone cage group and 23.2 months in the autologous iliac crest graft group. The operative time and intraoperative blood loss in group A were much less than those in group B (p < 0.05). All the patients in both groups got complete interbody fusion. Postoperative JOA scores in both group A and group B were more than the preoperative ones with significant differences, and the improvement rate of JOA scores had no statistical differences between group A and group B. Postoperative cervical physiological curvature and intervertebral height in both groups were better than the preoperative ones with statistical significances. CONCLUSIONS: The stand-alone PEEK cage is a good substitute for fusion in patients with cervical disc disease; it can effectively restore the cervical physiological curvature and the intervertebral height, facilitate radiological follow-up, cause few complications, and leads to satisfactory outcomes.