Ethno-demographic disparities in humoral responses to the COVID-19 vaccine among healthcare workers.

The COVID-19 pandemic had a profound impact on global health, but rapid vaccine administration resulted in a significant decline in morbidity and mortality rates worldwide. In this study, we sought to explore the temporal changes in the humoral immune response against SARS-CoV-2 healthcare workers (HCWs) in Augusta, GA, USA, and investigate any potential associations with ethno-demographic features. Specifically, we aimed to compare the naturally infected individuals with naïve individuals to understand the immune response dynamics after SARS-CoV-2 vaccination. A total of 290 HCWs were included and assessed prospectively in this study. COVID status was determined using a saliva-based COVID assay. Neutralizing antibody (NAb) levels were quantified using a chemiluminescent immunoassay system, and IgG levels were measured using an enzyme-linked immunosorbent assay method. We examined the changes in antibody levels among participants using different statistical tests including logistic regression and multiple correspondence analysis. Our findings revealed a significant decline in NAb and IgG levels at 8-12 months postvaccination. Furthermore, a multivariable analysis indicated that this decline was more pronounced in White HCWs (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.07-4.08, p = 0.02) and IgG (OR = 2.07, 95% CI = 1.04-4.11, p = 0.03) among the whole cohort. Booster doses significantly increased IgG and NAb levels, while a decline in antibody levels was observed in participants without booster doses at 12 months postvaccination. Our results highlight the importance of understanding the dynamics of immune response and the potential influence of demographic factors on waning immunity to SARS-CoV-2. In addition, our findings emphasize the value of booster doses to ensure durable immunity.

Reduction of SARS-CoV-2 salivary viral load with pre-procedural mouth rinses: a randomised, controlled, clinical trial.

Introduction The purpose of this study was to test the short-term efficacy of four commercial mouthwashes versus water in reducing SARS-CoV-2 viral load in the oral cavity over clinically relevant time points.Methods In total, 32 subjects that were proven SARS-CoV-2-positive via polymerase chain reaction (PCR)-based diagnostic test were recruited and randomised into five parallel arms. Cycle threshold (Ct) values were compared in saliva samples between the groups, as well as within the groups at baseline (pre-rinse), zero hours, one hour and two hours post-rinse, using SARS-CoV-2 reverse transcription-PCR analysis.Results We observed a significant increase in Ct values in saliva samples collected immediately after rinsing with all the four mouthwashes - 0.12% chlorhexidine gluconate, 1.5% hydrogen peroxide, 1% povidone iodine, or Listerine - compared to water. A sustained increase in Ct values for up to two hours was only observed in the Listerine and chlorohexidine gluconate groups. We were not able to sufficiently power this clinical trial, so the results remain notional but encouraging and supportive of findings in other emerging mouthwash studies on COVID-19, warranting additional investigations.Conclusions Our evidence suggests that in a clinical setting, prophylactic rinses with Listerine or chlorhexidine gluconate can potentially reduce SARS-CoV-2 viral load in the oral cavity for up to two hours. While limited in statistical power due to the difficulty in obtaining this data, we advocate for pre-procedural mouthwashing, like handwashing, as an economical and safe additional precaution to help mitigate the transmission of SARS-CoV-2 from a potentially infected patient to providers.

Sport participation, acculturative stress, and depressive symptoms among international college students in the United States.

Introduction: The distinctive social nature of sport in its capacity to promote immigrants' adaptation to the new society has been regarded as a vehicle to cope with adverse mental health outcomes derived from acculturative stress (AS) and feelings of marginalization. However, the evidence on the relationship between sport participation (SP), AS, and mental health have been lacking and fragmented. Recognizing this challenge, we examined the mediating effect of AS on the relationship between SP and depressive symptoms (DS) among international college students in the USA. Methods: A total of 203 international college students in the USA were recruited via Prolific. The instrumentation included previously validated measures: SP (SLIM-18), AS (ASSIS), DS (CES-D-10), sense of coherence (SOC-13), and demographic characteristics. Results: Mediation analysis showed a significant association between (1) SP and DS (ß = -0.030, p < 0.05) and (2) AS and DS (ß = 0.053, p < 0.001), while (3) no significant indirect effect of AS was found [ß = -0.001, SE = 0.0003, 95% CI (-0.008, 0.004)]. Discussion: Even though several previous scholars have argued that SP is an effective tool to cope with AS among international students, the present study implies this may not be applied to all international students. Specifically, AS and DS among European participants were lower than those from non-European countries, including Asia. Future studies using meta-analysis could be beneficial to examine the external validity of the previous studies on the relationship between SP, acculturation, and mental health to address this potential heterogeneity on the level of AS based on their origin countries or continents. The current study provides meaningful implications for adopting the transformative marketing perspective, which is a marketing approach that pursues positive social outcomes by promoting positive behavior of the target population.

Ovarian Combined Serous Borderline Tumor/Low-grade Serous Carcinoma and Mesonephric-like Lesion: Report of 2 Cases With New Observations.

Ovarian combined serous borderline tumor/low-grade serous carcinomas (SBT/LGSC) and mesonephric-like adenocarcinomas (MLA) have been previously reported and the presence of identical oncogenic somatic mutations in both components supports the concept that at least some of MLAs arise from a Müllerian origin. We report 2 cases of ovarian combined SBT/LGSC and mesonephric-like lesion. Case 1 was a 70-yr-old woman presented with a liver lesion and omental carcinomatosis. Histologic examination revealed biphasic tumors in bilateral ovaries consisting of conventional SBT and invasive MLA with extraovarian spread. The right ovary also had a component of cribriform variant of SBT/noninvasive LGSC. The SBT/LGSC component was diffusely positive for Pax8, WT-1, and ER, focally positive for PR, and negative for GATA3, while the MLA component was diffusely positive for GATA3 but negative for WT-1, ER, and PR. Molecular analysis revealed a KRAS G12V mutation in both the SBT/LGSC and MLA components, indicating their clonal origin. Case 2 was a 58-yr-old woman who presented with conventional type SBT in both ovaries. In addition, the left ovarian tumor demonstrated a few areas (each <5 mm) of mesonephric-like differentiation/hyperplasia in close proximity to the serous-type epithelium, with an immunophenotype of focal GATA3 expression, luminal pattern of CD10 staining and negative WT-1, ER, and PR staining. This phenomenon has been reported in endometrioid borderline tumor but not in any serous type lesions. The findings in case 1 provide further evidence to demonstrate the clonal relationship between these morphologically and immunophenotypically distinct components. It also supports the theory that, unlike cervical mesonephric carcinomas originating from mesonephric remnants, MLAs are derived from a Müllerian-type lesion with differentiation into mesonephric lineage. The presence of a hyperplastic mesonephric-like lesion/differentiation in case 2 indicates that a precursor lesion in the same lineage with the potential to develop into MLA exists in the ovary.

Pain Levels Did Not Differ Following Uncomplicated Third Molar Extractions Utilizing Liposomal Bupivacaine Versus Standard Bupivacaine.

PURPOSE: Operations in the oral cavity are often characterized by an acute period of postoperative pain historically mitigated via opioids and other analgesics. The purpose of the study was to determine if liposomal bupivacaine infiltration (LBI) following uncomplicated extraction of bilateral, mandibular third molars will significantly reduce postoperative pain when compared to standard bupivacaine. MATERIALS AND METHODS: The study was designed as a parallel-arm randomized clinical trial. The sample size was calculated for the primary outcome variable: postoperative pain levels measured at 48-hours. Using a power analysis, a sample size of n = 13 for each group was required. Patients meeting the inclusion/exclusion criteria requiring exodontia from November 4, 2018, to June 16, 2022, were recruited out of the oral and maxillofacial surgery clinic. The patients were randomized and divided into 2 groups. Group A was administered 0.50% bupivacaine (with 1:200,000 epinephrine) via infiltration while group B underwent LBI. The primary outcome of interest was postoperative pain levels followed by the secondary outcomes of postoperative narcotic analgesic use, return to oral function, and satisfaction. Patient demographics and characteristics were analyzed as potential covariates utilizing the Fisher exact test and t test for continuous outcomes, respectively. RESULTS: Thirty patients were recruited for the study. The average age of patients receiving the third molar operation was 24.1 ± 5.8 years. Of the 30, 62.5% were female, and 37.5% were male. Seventy-five percent of the patients were Caucasian, 20.8% were African American, and 4.2% were Asian. Forty-eight-hour postoperative interviews revealed mean pain levels of 2.5 ± 2.8 in the control group and 2.9 ± 2.3 in the LBI group (P = .730) as measured on a visual analog scale. The 48-hour postoperative interview identified a mean of 1.9 ± 2.1 narcotic pills used in the control group and 2.5 ± 5.0 pills used in the LBI group (P = .693). CONCLUSIONS: Mandibular LBIs following bilateral mandibular third molar extractions showed no statistically significant advantage over the standard bupivacaine at either time point analyzed. Furthermore, no statistically significant difference was found regarding narcotic use between the 2 groups.

Does a Difference Exists in Comprehensive Basic Science Examination Scores of 4-Year versus 6-Year Oral-Maxillofacial Surgery Residents?

PURPOSE: The Comprehensive Basic Science Examination (CBSE) scores have significant effects on the applications of oral-maxillofacial surgery (OMS) residency candidates. However, a comparison of the scores of residents that match to 4-year versus 6-year programs is lacking. The present study compared the CBSE scores of OMS residency candidates who had matched to 4-year and 6-year tracks in the 2018-2019 application cycle. MATERIALS AND METHODS: In the present cross-sectional analysis, an anonymous questionnaire was sent electronically to program directors of all OMS residency programs in the United States using the online survey engine Survey Monkey. Data were collected on the CBSE scores of their postgraduate year 1 categorical residents and whether the resident was on a 4-year or 6-year track. The CBSE scores were summarized overall and by the type of residency program (4 vs 6 year) using the mean, standard deviation, median, mode, minimum, and maximum. In addition, the 2-sample t test was used to compare the mean CBSE score between the 4-year programs (4YPs) and 6-year programs (6YPs). RESULTS: A total of 37 scores were received from the 4YPs and 31 from the 6YPs. The overall mean CBSE score was 68.9. Using the 2-sample t test, the mean CBSE score differed significantly between the 4YPs and 6YPs (t = -6.59; df = 66; P < .0001). CONCLUSIONS: Candidates matching into 6-year positions showed significantly higher mean scores on the CBSE examination compared with those matching into 4-year positions.

Time to Open Repair of Mandibular Fractures and Associated Complications.

PURPOSE: The aim of this study was to determine whether a correlation exists between the time from injury to repair of mandibular fractures and the development of postoperative complications. We also sought to assess whether a delay in treatment manifests in an increased surgical time. PATIENTS AND METHODS: We performed a retrospective cohort study and enrolled a sample (N = 64) derived from patients treated with open repair of mandibular fractures at Augusta University Medical Center by the oral and maxillofacial surgery service from July 2015 to June 2018. Time from injury to surgical repair was analyzed as a continuous variable, and the primary outcome was the presence of any of the following postoperative complications: infection, mechanical complication, cranial nerve V3 deficit, or cranial nerve VII deficit. Secondary outcome variables included the presence of substance abuse, surgical approach, and surgery time. Logistical regression was performed. RESULTS: Among 64 patients, there were 27 patients with a total of 32 complications, including infection (n = 9), mechanical complications (n = 3), cranial nerve V3 deficits (n = 13), and cranial nerve VII deficits (n = 7). The mean time to fixation was 13.26 days in patients without complications versus 17.52 days in patients with complications. The association between time to surgical repair and complication rate was not statistically significant (P = .203). No association was found between time to surgical repair and surgery time (P = .699). CONCLUSIONS: Our study did not find a significant association between the timing of repair of mandibular fractures and complications. Our study also failed to show a correlation between a delay in surgical intervention and increased technical challenges manifested by an increased surgical time.

Evaluation of Crystal Zenith Microtiter Plates for High-Throughput Formulation Screening.

Formulation screening for biotherapeutics can cover a vast array of excipients and stress conditions. These studies consume quantities of limited material and, with higher concentrated therapeutics, more material is needed. Here, we evaluate the use of crystal zenith (CZ) microtiter plates in conjunction with FluoroTec-coated butyl rubber mats as a small-volume, high-throughput system for formulation stability studies. The system was studied for evaporation, edge effects, and stability with comparisons to type 1 glass and CZ vials for multiple antibodies and formulations. Evaporation was minimal at 4°C and could be reduced at elevated temperatures using sealed, mylar bags. Edge effects were not observed until 12 weeks at 40°C. The overall stability ranking as measured by the rate of change in high molecular weight and percent main peak species was comparable across both vials and plates at 4°C and 40°C out to 12 weeks. Product quality attributes as measured by the multi-attribute method were also comparable across all containers for each molecule formulation. A potential difference was measured for subvisible particle analysis, with the plates measuring lower particle counts than the vials. Overall, CZ plates are a viable alternative to traditional vials for small-volume, high-throughput formulation stability screening studies.

A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery.

OBJECTIVE: To determine which non-narcotic analgesic, acetaminophen (Ofirmev®) or ketorolac (Toradol®), provides better post-operative pain control when combined with an opioid patient-controlled analgesia (PCA) pump. Secondary objectives include comparisons of the rates of ileus, post-operative bleeding, transfusions, and length-of-hospitalization (LOH). METHODS: A prospective, randomized trial of acetaminophen (A) 1-g intravenous (IV) every 6-h or ketorolac (K) 15-mg IV every 6-h from post-operative day 1-3 in addition to an opioid PCA for patients undergoing benign or malignant gynecologic laparotomy procedures was performed. Abstracted data included pain levels via visual analogue pain scales (VAS), amount of narcotic used, hepatic enzyme levels, hemoglobin, urine output, blood transfusions, time to return of flatus and LOH. RESULTS: One-hundred patients were accrued and underwent 55 benign gynecologic laparotomies and 45 cancer-related laparotomies. VAS pain levels (3.3 K, 3.5 A) and morphine PCA use (79.1 oral morphine equivalents [OME] K vs. 84.5 A) were not different, however dilaudid PCA usage was less by K patients (84.4 OME K and 136.8 OME A, p < 0.001). There was a significant hemoglobin change between the two groups (2.6 g K vs. 2 g A, p = 0.015), however blood transfusions were equal (28% K, 22% A, p > 0.05). Return of flatus was 2.7-days for K vs. 3.4-days for A (p = 0.011) and LOH was not different (4.4-days K vs. 5.1-days A, p = 0.094). CONCLUSIONS: Both intravenous ketorolac and acetaminophen provide similar post-operative analgesia through VAS pain scales and total usage of morphine via PCA pumps. Use of ketorolac with dilaudid PCA was associated with less dependence on dilaudid and a quicker return of bowel function than acetaminophen, however length of stay and transfusion rates were not different.

Impact of acute sleep restriction on cerebral glucose metabolism during recovery non-rapid eye movement sleep among individuals with primary insomnia and good sleeper controls.

BACKGROUND: Restricting time in bed improves insomnia symptoms, but the neural mechanisms for this effect are unknown. Total and partial acute sleep restriction may be useful paradigms for elucidating these effects. We examined the impact of acute sleep restriction on cerebral glucose metabolism during non-rapid eye movement (NREM) sleep in individuals with primary insomnia (n = 17) and good sleep (n = 19). METHODS: Participants underwent [18F]fluorodeoxyglucose positron emission tomography scans during baseline and recovery NREM sleep following one night of partial or total sleep restriction. We compared group differences in baseline-recovery changes, as well as main effects of group and condition (baseline vs. recovery NREM sleep), for relative regional cerebral metabolic rate for glucose (rCMRglc), whole-brain glucose metabolism, and sleep quality. RESULTS: Relative rCMRglc was significantly lower during recovery NREM sleep compared to baseline in the left frontoparietal cortex, medial frontal cortex, posterior cingulate cortex, and thalamus, with no significant group differences. Good sleepers, but not insomnia patients, had lower whole-brain glucose metabolism during recovery NREM sleep compared to baseline. Acute sleep restriction improved sleep quality in individual with insomnia. Subgroup analyses including only participants who underwent partial sleep restriction yielded the same pattern of findings. CONCLUSION: Individuals with insomnia and good sleepers showed similar relative rCMRglc responses to acute sleep restriction. Brain regions showing the greatest baseline-recovery changes in both groups included regions previously shown to have smaller sleep-wake differences in patients with primary insomnia. Acute sleep restriction, and by extension sleep restriction therapy, may impact regional metabolic alterations that characterize insomnia.

Subjective-Objective Sleep Discrepancy Is Associated With Alterations in Regional Glucose Metabolism in Patients With Insomnia and Good Sleeper Controls.

Objectives: Sleep discrepancies are common in primary insomnia (PI) and include reports of longer sleep onset latency (SOL) than measured by polysomnography (PSG) or "negative SOL discrepancy." We hypothesized that negative SOL discrepancy in PI would be associated with higher relative glucose metabolism during nonrapid eye movement (NREM) sleep in brain networks involved in conscious awareness, including the salience, left executive control, and default mode networks. Methods: PI (n = 32) and good sleeper controls (GS; n = 30) completed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans during NREM sleep, and relative regional cerebral metabolic rate for glucose (rCMRglc) was measured. Sleep discrepancy was calculated by subtracting PSG-measured SOL on the PET night from corresponding self-report values the following morning. We tested for interactions between group (PI vs. GS) and SOL discrepancy for rCMRglc during NREM sleep using both a region of interest mask and exploratory whole-brain analyses. Results: Significant group by SOL discrepancy interactions for rCMRglc were observed in several brain regions (pcorrected < .05 for all clusters). In the PI group, more negative SOL discrepancy (self-reported > PSG-measured SOL) was associated with significantly higher relative rCMRglc in the right anterior insula and middle/posterior cingulate during NREM sleep. In GS, more positive SOL discrepancy (self-reported < PSG-measured SOL) was associated with significantly higher relative rCMRglc in the right anterior insula, left anterior cingulate cortex, and middle/posterior cingulate cortex. Conclusions: Although preliminary, these findings suggest regions of the brain previously shown to be involved in conscious awareness, and the perception of PSG-defined states may also be involved in the phenomena of SOL discrepancy.

Sleep-Wake Differences in Relative Regional Cerebral Metabolic Rate for Glucose among Patients with Insomnia Compared with Good Sleepers.

STUDY OBJECTIVES: The neurobiological mechanisms of insomnia may involve altered patterns of activation across sleep-wake states in brain regions associated with cognition, self-referential processes, affect, and sleep-wake promotion. The objective of this study was to compare relative regional cerebral metabolic rate for glucose (rCMRglc) in these brain regions across wake and nonrapid eye movement (NREM) sleep states in patients with primary insomnia (PI) and good sleeper controls (GS). METHODS: Participants included 44 PI and 40 GS matched for age (mean = 37 y old, range 21-60), sex, and race. We conducted [18F]fluoro-2-deoxy-D-glucose positron emission tomography scans in PI and GS during both morning wakefulness and NREM sleep at night. Repeated measures analysis of variance was used to test for group (PI vs. GS) by state (wake vs. NREM sleep) interactions in relative rCMRglc. RESULTS: Significant group-by-state interactions in relative rCMRglc were found in the precuneus/posterior cingulate cortex, left middle frontal gyrus, left inferior/superior parietal lobules, left lingual/fusiform/occipital gyri, and right lingual gyrus. All clusters were significant at Pcorrected < 0.05. CONCLUSIONS: Insomnia was characterized by regional alterations in relative glucose metabolism across NREM sleep and wakefulness. Significant group-by-state interactions in relative rCMRglc suggest that insomnia is associated with impaired disengagement of brain regions involved in cognition (left frontoparietal), self-referential processes (precuneus/posterior cingulate), and affect (left middle frontal, fusiform/lingual gyri) during NREM sleep, or alternatively, to impaired engagement of these regions during wakefulness.

Prenatal Counseling, Ultrasound Diagnosis, and the Role of Maternal-Fetal Medicine of the Cleft Lip and Palate Patient.

A multidisciplinary team is the standard of care and the cornerstone of management of cleft patients. With readily improving advanced diagnostic modalities, early prenatal diagnosis of cleft lip and palate increasingly becomes a topic of importance for both the team caring for and families of cleft patients. Maternal-fetal medicine is a fellowship subspecialty of obstetrics that can offer high-quality care and coordination to the cleft team. Both 3-D and 4-D sonography lead to early prenatal diagnosis of cleft patients; however, differences in training result in variations in its diagnostic accuracy.

The role of non-rapid eye movement slow-wave activity in prefrontal metabolism across young and middle-aged adults.

Electroencephalographic slow-wave activity (0.5-4 Hz) during non-rapid eye movement (NREM) sleep is a marker for cortical reorganization, particularly within the prefrontal cortex. Greater slow wave activity during sleep may promote greater waking prefrontal metabolic rate and, in turn, executive function. However, this process may be affected by age. Here we examined whether greater NREM slow wave activity was associated with higher prefrontal metabolism during wakefulness and whether this relationship interacted with age. Fifty-two participants aged 25-61 years were enrolled into studies that included polysomnography and a (18) [F]-fluoro-deoxy-glucose positron emission tomography scan during wakefulness. Absolute and relative measures of NREM slow wave activity were assessed. Semiquantitative and relative measures of cerebral metabolism were collected to assess whole brain and regional metabolism, focusing on two regions of interest: the dorsolateral prefrontal cortex and the orbitofrontal cortex. Greater relative slow wave activity was associated with greater dorsolateral prefrontal metabolism. Age and slow wave activity interacted significantly in predicting semiquantitative whole brain metabolism and outside regions of interest in the posterior cingulate, middle temporal gyrus and the medial frontal gyrus, such that greater slow-wave activity was associated with lower metabolism in the younger participants and greater metabolism in the older participants. These results suggest that slow-wave activity is associated with cerebral metabolism during wakefulness across the adult lifespan within regions important for executive function.

Surgical anatomy and utility of pedicled vascularized tissue flaps for multilayered repair of skull base defects.

OBJECT The objective of this study was to describe the surgical anatomy and technical nuances of various vascularized tissue flaps. METHODS The surgical anatomy of various tissue flaps and their vascular pedicles was studied in 5 colored silicone-injected anatomical specimens. Medical records were reviewed of 11 consecutive patients who underwent repair of extensive skull base defects with a combination of various vascularized flaps. RESULTS The supraorbital, supratrochlear, superficial temporal, greater auricular, and occipital arteries contribute to the vascular supply of the pericranium. The pericranial flap can be designed based on an axial blood supply. Laterally, various flaps are supplied by the deep or superficial temporal arteries. The nasoseptal flap is a vascular pedicled flap based on the nasoseptal artery. Patients with extensive skull base defects can undergo effective repair with dual flaps or triple flaps using these pedicled vascularized flaps. CONCLUSIONS Multiple pedicled flaps are available for reconstitution of the skull base. Knowledge of the surgical anatomy of these flaps is crucial for the skull base surgeon. These vascularized tissue flaps can be used effectively as single or combination flaps. Multilayered closure of cranial base defects with vascularized tissue can be used safely and may lead to excellent repair outcomes.

Extensive traumatic anterior skull base fractures with cerebrospinal fluid leak: classification and repair techniques using combined vascularized tissue flaps.

OBJECTIVE: This article introduces a classification scheme for extensive traumatic anterior skull base fracture to help stratify surgical treatment options. The authors describe their multilayer repair technique for cerebrospinal fluid (CSF) leak resulting from extensive anterior skull base fracture using a combination of laterally pediculated temporalis fascial-pericranial, nasoseptal-pericranial, and anterior pericranial flaps. METHODS: Retrospective chart review identified patients treated surgically between January 2004 and May 2014 for anterior skull base fractures with CSF fistulas. All patients were treated with bifrontal craniotomy and received pedicled tissue flaps. Cases were classified according to the extent of fracture: Class I (frontal bone/sinus involvement only); Class II (extent of involvement to ethmoid cribriform plate); and Class III (extent of involvement to sphenoid bone/sinus). Surgical repair techniques were tailored to the types of fractures. Patients were assessed for CSF leak at follow-up. The Fisher exact test was applied to investigate whether the repair techniques were associated with persistent postoperative CSF leak. RESULTS: Forty-three patients were identified in this series. Thirty-seven (86%) were male. The patients' mean age was 33 years (range 11-79 years). The mean overall length of follow-up was 14 months (range 5-45 months). Six fractures were classified as Class I, 8 as Class II, and 29 as Class III. The anterior pericranial flap alone was used in 33 patients (77%). Multiple flaps were used in 10 patients (3 salvage) (28%)--1 with Class II and 9 with Class III fractures. Five (17%) of the 30 patients with Class II or III fractures who received only a single anterior pericranial flap had persistent CSF leak (p < 0.31). No CSF leak was found in patients who received multiple flaps. Although postoperative CSF leak occurred only in high-grade fractures with single anterior flap repair, this finding was not significant. CONCLUSIONS: Extensive anterior skull base fractures often require aggressive treatment to provide the greatest long-term functional and cosmetic benefits. Several vascularized tissue flaps can be used, either alone or in combination. Vascularized flaps are an ideal substrate for cranial base repair. Dual and triple flap techniques that combine the use of various anterior, lateral, and nasoseptal flaps allow for a comprehensive arsenal in multilayered skull base repair and salvage therapy for extensive and severe fractures.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study.

BACKGROUND: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. METHODS: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid ß (Aß) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). FINDINGS: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. INTERPRETATION: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aß accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aß deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. FUNDING: National Institutes of Health and Howard Hughes Medical Institute.

Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals.

IMPORTANCE: Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. OBJECTIVE: To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, ß-amyloid (Aß), and cognition. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. INTERVENTIONS: 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aß. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. MAIN OUTCOMES AND MEASURES: Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aß were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. RESULTS: The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60). CONCLUSIONS AND RELEVANCE: In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.