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Objective: To determine whether physicians who interact with their patients between office visits using secure messaging and phone provide better care for patients with diabetes when controlling for physician, patient and care center characteristics.Design: Retrospective study.Setting: Kaiser Permanente Mid-Atlantic States.Participants: 174 Primary Care Physicians.Intervention: We modeled the relationship between communication via secure messaging or phone communication and Diabetes Recognition Program (DRP) scores with a Generalized Estimating Equations model. Covariates included physician age and panel size, patient age, race, income and number of comorbidities, and the population density around the care center.Main Outcome Measure: DRP scores.Results: Physicians whose patients were predominantly white or mixed race were more likely than other physicians to use secure messaging and phone with their patients between visits, but there was no significant association between such contacts and DRP scores (P> 0.1). In contrast, physicians with predominantly black or Hispanic patients had significantly higher DRP scores associated with the use of secure messaging (P< 0.01) and higher, though not statistically significant, DRP scores associated with the use of phone (P< 0.1). These associations were strongest for outcome measures such as HbA1c and lipid levels, and were weaker or nonexistent for process measures such as annual foot and eye exams.Conclusions: The use of secure messaging, and, to a lesser extent, phone, appears to be associated with higher quality diabetes care, particularly among at-risk populations. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia is a common complication following endoscopic endonasal resection (EER) of pituitary adenomas. We report a single-center, multisurgeon study detailing baseline clinical data, outcomes, and factors associated with postoperative hyponatremia., Methods: This was a retrospective cohort study of patients undergoing EER for pituitary adenoma at Tufts Medical Center. Most procedures were performed by the senior author (C.B.H.). Cases were included if at least 1 postoperative sodium value was available and pathology confirmed pituitary adenoma. Hyponatremia was defined as a postoperative sodium level <135 mEq/L., Results: A total of 272 patients underwent 310 EER procedures that met the study inclusion criteria. The mean patient age was 53.3 years, and mean tumor size was 18.8 mm. Postoperative hyponatremia occurred in 12.6% of cases, with 3.6% developing hyponatremia prior to discharge. Lower preoperative sodium level was associated with an increased risk of developing any postoperative hyponatremia. Older age, prolactinoma pathology, and use of selective serotonin reuptake inhibitors were associated with moderate to severe hyponatremia (≤129 mEq/L), and lower preoperative sodium was associated with mild hyponatremia (130-134 mEq/L). Hyponatremia-related readmissions within 30 days occurred in 3.9% of patients. Both African-American race and postoperative hyponatremia were associated with an increased risk of 30-day readmission. The mean nadir sodium for hyponatremic patients was 129.9 mEq/L. Growth hormone-secreting pathology was associated with lower postoperative nadir sodium, whereas higher preoperative sodium was associated with higher postoperative nadir sodium., Conclusions: Hyponatremia is a common postoperative complication of EER for pituitary lesions that can cause significant morbidity, increased readmissions, and increased healthcare costs., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Arteriovenous malformations (AVMs) are vascular malformations that are more commonly found intracranially, followed by the head, neck, limbs, and trunk. Extracranially, AVMs can mimic peripheral nerve tumors, leading to misdiagnosis., Observations: A 19-year-old female, who presented with left lateral lower leg pain, was preoperatively thought to have a peripheral nerve tumor; at surgery, however, she was found to have an extracranial AVM. The distinct margins of the tumor on preoperative magnetic resonance imaging suggested that the patient might have a peripheral nerve tumor; however, the clinical symptoms of focal pain at rest and the absence of Tinel's sign should have raised questions about this diagnosis., Lessons: This case highlights the difficulty in differentiating a peripheral nerve tumor from an extracranial AVM in certain clinical scenarios. It is important to use a multifaceted diagnostic approach to get a correct preoperative diagnosis and plan treatment appropriately.

Background and Objectives: Several neurosurgical pathologies, ranging from glioblastoma to hemorrhagic stroke, use volume thresholds to guide treatment decisions. For chronic subdural hematoma (cSDH), with a risk of retreatment of 10%-30%, the relationship between preoperative and postoperative cSDH volume and retreatment is not well understood. We investigated the potential link between preoperative and postoperative cSDH volumes and retreatment., Methods: We performed a retrospective chart review of patients operated for unilateral cSDH from 4 level 1 trauma centers, February 2009-August 2021. We used a 3-dimensional deep learning, automated segmentation pipeline to calculate preoperative and postoperative cSDH volumes. To identify volume thresholds, we constructed a receiver operating curve with preoperative and postoperative volumes to predict cSDH retreatment rates and selected the threshold with the highest Youden index. Then, we developed a light gradient boosting machine to predict the risk of cSDH recurrence., Results: We identified 538 patients with unilateral cSDH, of whom 62 (12%) underwent surgical retreatment within 6 months of the index surgery. cSDH retreatment was associated with higher preoperative (122 vs 103 mL; P < .001) and postoperative (62 vs 35 mL; P < .001) volumes. Patients with >140 mL preoperative volume had nearly triple the risk of cSDH recurrence compared with those below 140 mL, while a postoperative volume >46 mL led to an increased risk for retreatment (22% vs 6%; P < .001). On multivariate modeling, our model had an area under the receiver operating curve of 0.76 (95% CI: 0.60-0.93) for predicting retreatment. The most important features were preoperative and postoperative volume, platelet count, and age., Conclusion: Larger preoperative and postoperative cSDH volumes increase the risk of retreatment. Volume thresholds may allow identification of patients at high risk of cSDH retreatment who would benefit from adjunct treatments. Machine learning algorithm can quickly provide accurate estimates of preoperative and postoperative volumes., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background and Objectives: An international, multicenter, retrospective study was conducted to evaluate the long-term clinical outcomes and tumor control rates after stereotactic radiosurgery (SRS) for trigeminal schwannoma., Methods: Patient data (N = 309) were collected from 14 international radiosurgery centers. The median patient age was 50 years (range 11-87 years). Sixty patients (19%) had prior resections. Abnormal facial sensation was the commonest complaint (49%). The anatomic locations were root (N = 40), ganglion (N = 141), or dumbbell type (N = 128). The median tumor volume was 4 cc (range, 0.2-30.1 cc), and median margin dose was 13 Gy (range, 10-20 Gy). Factors associated with tumor control, symptom improvement, and adverse radiation events were assessed., Results: The median and mean time to last follow-up was 49 and 65 months (range 6-242 months). Greater than 5-year follow-up was available for 139 patients (45%), and 50 patients (16%) had longer than 10-year follow-up. The overall tumor control rate was 94.5%. Tumors regressed in 146 patients (47.2%), remained unchanged in 128 patients (41.4%), and stabilized after initial expansion in 20 patients (6.5%). Progression-free survival rates at 3 years, 5 years, and 10 years were 91%, 86%, and 80 %. Smaller tumor volume (less than 8 cc) was associated with significantly better progression-free survival ( P = .02). Seventeen patients with sustained growth underwent further intervention at a median of 27 months (3-144 months). Symptom improvement was noted in 140 patients (45%) at a median of 7 months. In multivariate analysis primary, SRS ( P = .003) and smaller tumor volume ( P = .01) were associated with better symptom improvement. Adverse radiation events were documented in 29 patients (9%)., Conclusion: SRS was associated with long-term freedom (10 year) from additional management in 80% of patients. SRS proved to be a valuable salvage option after resection. When used as a primary management for smaller volume tumors, both clinical improvement and prevention of new deficits were optimized., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: The diagnosis of hydrocephalus is dependent on clinical symptoms and radiographic findings including ventriculomegaly. Our goal was to generate a data set of ventricular volume utilizing non-pathologic computed tomography (CT) scans for adults to help define reference ventricle size., Methods: We performed a retrospective analysis of non-contrast head CTs for adults at a single institution to identify patients who had undergone imaging and did not have a diagnosis of hydrocephalus, history of ventriculoperitoneal shunting, or treatments for hydrocephalus. A convolutional neural network was trained on hand-segmented scans from a variety of age ranges and then utilized to automate the segmentation of the entire data set., Results: Ventricles on 866 CT scans were segmented to generate a reference range of volumes for both male and female individuals ranging in age from 18-99 years. The generated data were binned by age ranges., Conclusions: We have developed a convolutional neural network that can segment the ventricles on CT scans of adult patients over a range of ages. This network was used to measure the ventricular volume of non-pathologic head CTs to produce reference ranges for several age bins. This data set could be utilized to aid in the diagnosis of hydrocephalus by comparing potentially pathologic scans to reference ventricular volumes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Primary spinal cord astrocytomas are rare, fatal, and poorly studied., Methods: This study included a 2-center, retrospective analysis of primary spinal cord astrocytoma patients from 1997 to 2020. Patients with drop metastases or without at least one follow-up were excluded., Results: Seven World Health Organization grade I, 6 grade II, 7 grade III, and 4 grade IV astrocytoma patients were included. Older patients had higher grades (median 20 years in grade I vs. 36.5 in grade IV). The median follow-up was 15 months. Thirteen patients were discharged to rehabilitation. Eight patients demonstrated radiographic progression. Adjuvant therapy was utilized more in higher grades (5 of 13 grades III vs. all 11 grades IIIIV). Six patients died (1 death in grades III vs. 5 in grades IIIIV). Ten patients had worsened symptoms at the last follow-up. The median progression-free survival in grade I, II, III, and IV tumors was 116, 36, 8, and 8.5 months, respectively. The median overall survival in grade I, II, III, and IV tumors was 142, 69, 19, and 12 months, respectively. Thrombotic complications occurred in 2 patients, one with isocitrate dehydrogenasewild type glioblastoma., Conclusions: Outcomes worsen with higher grades and lead to difficult postoperative periods. Clinicians should be vigilant for thromboembolic complications. Further research is needed to understand these rare tumors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The overall safety and efficacy of flow diverting stents (FDSs) deployed in small caliber parent arteries (≤2.5 mm) for the treatment of intracranial aneurysms remains unclear. Recent studies have provided additional outcomes data to assess the use of FDSs for such arteries. In the present review, we have summarized the reported clinical and angiographic outcomes of FDS-treated brain aneurysms in small parent arteries., Methods: A systematic literature review was performed for outcomes data related to FDS-treated intracranial aneurysms using PubMed, Ovid Medline, and Web of Science. Procedural data, angiographic outcomes, and clinical outcomes at various time points were collected and summarized., Results: The 19 studies included 580 patients with 604 aneurysms, of which 6.1% had been acutely ruptured and 28.3% had been previously treated. The procedural complication rate and symptomatic stroke rate was 9.8% and 7.5%. The complete occlusion rate at the last radiographic follow-up (mean, 12.1 months) was 73.6%. At the last clinical follow-up (mean, 10.6 months), the FDS-associated mortality was 2.5%., Conclusions: FDSs for the treatment of intracranial aneurysms located in small caliber arteries was associated with rates of long-term complete aneurysm occlusion, mortality, and permanent neurologic deficit comparable to the rates with FDS-treated aneurysms in larger parent arteries. However, the relatively increased risk of symptomatic stroke of these FDS-treated aneurysms should not be ignored. Direct comparisons with alternative endovascular approaches are necessary to further define the optimal use of FDS for these aneurysms., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: In this article, the authors describe the impact of the COVID-19 virtual match cycle and discuss approaches to optimize future cycles through applicant and neurosurgical education leadership insights., Methods: Anonymous surveys of neurosurgery program leaders (program directors and program chairs), program administrators (PAs), and 2020-2021 neurosurgery residency match applicants were distributed by the SNS, in conjunction with the Association of Resident Administrators in Neurological Surgery and AANS Young Neurosurgeons Committee., Results: Responses were received from 77 (67.0%) of 115 PAs, 119 (51.7%) of 230 program leaders, and 124 (44.3%) of 280 applicants representing geographically diverse regions. During the virtual application cycle relative to the previous year, programs received more Electronic Residency Application Service applications (mean 314.8 vs 285.3, p < 0.0001) and conducted more applicant interviews (mean 45.2 vs 39.9, p = 0.0003). More than 50% of applicants applied to > 80 programs; 60.3% received ≤ 20 interview invitations, and 9% received > 40 invitations. Overall, 65% of applicants completed ≤ 20 interviews, whereas 34.7% completed > 20 interviews. Program leaders described one 4-week home subinternship (93.3%) and two 4-week external subinternships (68.9%) as optimal neurosurgical exposure; 62.8% of program leaders found the standardized letter of recommendation template to be somewhat (47.5%) or significantly (15.3%) helpful. Applicants, PAs, and program leaders all strongly preferred a hybrid model of in-person and virtual interview options for future application cycles over all in-person or all virtual options. Ninety-three percent of applicants reported matching within their top 10-ranked programs, and 52.9% of programs matched residents within the same decile ranking as in previous years., Conclusions: Optimizing a national strategy for the neurosurgery application process that prioritizes equity and reduces costs, while ensuring adequate exposure for applicants to gain educational opportunities and evaluate programs, is critical to maintain a successful training system.

Intracranial meningeal convexity chondroma is a rare benign lesion hypothesized to stem from remnant chondrocyte precursors of embryonic origin. This lesion often masquerades as meningioma given the similar dural-based attachment and pattern of calcification. We describe the case of a 26-year-old female with incidentally discovered convexity meningeal chondroma, originally presumed to be a meningioma. In this case, we share our diagnostic and operative intervention and outcome and discuss the unique pathologic findings in this lesion that differentiate it from similar appearing lesions. To the authors' knowledge, there are fewer than 20 cases of convexity meningeal chondroma in the literature; thus, we also provide a brief review of the literature regarding this rare pathology., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Sarathy et al.)

Objective: The long-term safety and efficacy of intrasaccular flow disruption (IFD) for the treatment of brain aneurysms remain unclear. With accumulating experience and increasing use of IFD devices, recent studies have provided additional data regarding their outcomes. This review summarizes the long-term outcomes of IFD-treated brain aneurysms., Methods: A systematic literature review was performed on May 23, 2021, in PubMed, Web of Science, and Ovid MEDLINE for aneurysm treatment outcomes with IFD devices. Procedural details, including use of adjunctive devices and complications, were collected. The quality of studies was assessed using the Downs and Black checklist. Angiographic outcomes were classified as complete occlusion, residual neck, and residual aneurysm. Other outcomes included need for retreatment, permanent neurological deficit, and mortality. Pooled analyses were performed., Results: The final analysis comprised 1217 patients with 1249 aneurysms from 22 studies. The mean aneurysm diameter and neck width were 6.9 and 4.5 mm, respectively, and 27.6% of aneurysms were ruptured. The complete occlusion rates at 12 months and final follow-up (pooled mean duration 15.7 months) were 50.1% and 58.2%, respectively. Adjunctive devices were used in 6.4% of cases. The rates of hemorrhage, symptomatic infarction, permanent neurological deficit, and mortality were 1.2%, 2.8%, 1.0%, and 2.6%, respectively., Conclusions: IFD is a very safe treatment for appropriately selected brain aneurysms with low complication and neurological deterioration rates. However, complete occlusion is achieved in only half of IFD-treated aneurysms at 1 year with a modest increase beyond this time point. As the majority of the studies were single arm, the pooled data are subject to selection and reporting biases. Future device developments, increased operator experience, and direct comparisons with alternative endovascular strategies and surgical clipping may clarify the role of IFD in aneurysm management.

Objective: The COVID-19 pandemic caused a significant disruption to residency recruitment, including a sudden, comprehensive transition to virtual interviews. The authors sought to characterize applicant experiences and perceptions concerning the change in the application, interview, and match process for neurological surgery residency during the 2020-2021 recruitment cycle., Methods: A national survey of neurosurgical residency applicants from the 2020-2021 application cycle was performed. This survey was developed in cooperation with the Society of Neurological Surgeons (SNS) and the American Association of Neurological Surgeons Young Neurosurgeons Committee (YNC) and sent to all applicants (n = 280) who included academic video submissions to the SNS repository as part of their application package. These 280 applicants accounted for 69.6% of the total 402 neurosurgical applicants this year., Results: Nearly half of the applicants responded to the survey (44.3%, 124 of 280). Applicants favored additional reform of the interview scheduling process, including a centralized scheduling method, a set of standardized release dates for interview invitations, and interview caps for applicants. Less than 8% of students desired a virtual-only platform in the future, though the majority of applicants supported incorporating virtual interviews as part of the process to contain applicant costs and combining them with traditional in-person interview opportunities. Program culture and fit, as well as clinical and research opportunities in subspecialty areas, were the most important factors applicants used to rank programs. However, subjective program "fit" was deemed challenging to assess during virtual-only interviews., Conclusions: Neurosurgery resident applicants identified standardized interview invitation release dates, centralized interview scheduling methods, caps on the number of interviews available to each candidate, and regulated opportunities for both virtual and in-person recruitment as measures that could significantly improve the applicant experience during and effectiveness of future neurosurgery residency application cycles. Applicants prioritized program culture and "fit" during recruitment, and a majority were open to incorporating virtual elements into future cycles to reduce costs while retaining in-person opportunities to gauge programs and their locations.

Objective: A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) suggested that medical management afforded outcomes superior to those following intervention for unruptured arteriovenous malformations (AVMs), but its findings have been controversial. Subsequent studies of AVMs that would have met the eligibility requirements of ARUBA have supported intervention for the management of some cases. The present meta-analysis was conducted with the object of summarizing interventional outcomes for ARUBA-eligible patients reported in the literature., Methods: A systematic literature search (PubMed, Web of Science, Google Scholar) for AVM intervention studies that used inclusion criteria identical to those of ARUBA (age ≥ 18 years, no history of AVM hemorrhage, no prior intervention) was performed. The primary outcome was death or symptomatic stroke. Secondary outcomes included AVM obliteration, hemorrhage, death, and poor outcome (modified Rankin Scale score ≥ 2 at final follow-up). Bias assessment was performed with the Newcastle-Ottawa Scale, and the results were synthesized as pooled proportions., Results: Of the 343 articles identified through database searches, 13 studies met the inclusion criteria, yielding an overall study cohort of 1909 patients. The primary outcome occurred in 11.2% of patients (pooled = 11%, 95% CI 8%-13%). The rates of AVM obliteration, hemorrhage, poor outcome, and death were 72.7% (pooled = 78%, 95% CI 70%-85%), 8.4% (pooled = 8%, 95% CI 6%-11%), 9.9% (pooled = 10%, 95% CI 7%-13%), and 3.5% (pooled = 2%, 95% CI 1%-4%), respectively. Annualized primary outcome and hemorrhage risks were 1.85 (pooled = 2.05, 95% CI 1.31-2.94) and 1.34 (pooled = 1.41, 95% CI 0.83-2.13) per 100 patient-years, respectively., Conclusions: Intervention for unruptured AVMs affords acceptable outcomes for appropriately selected patients. The risk of hemorrhage following intervention compared favorably to the natural history of unruptured AVMs. The included studies were retrospective and varied in treatment and AVM characteristics, thereby limiting the generalizability of their data. Future studies from prospective registries may clarify patient, nidus, and intervention selection criteria that will refine the challenging management of patients with unruptured AVMs.

Objective: Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH., Methods: A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist., Results: The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02)., Conclusions: APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting.

Background: Skull base leiomyomas (LMs) and angioleiomyomas (ALMs) are rare, and the understanding of this disease is limited. We present a systematic literature review of skull base LM and ALM and report a case of internal auditory canal (IAC) ALM., Methods: A systematic review was conducted following the PRISMA guidelines. PubMed and Embase were systematically queried for skull base LM and ALM, and Rayyan QCRI was used for the review. After applying exclusion criteria, individual articles were evaluated for quality control, data collection, and analysis. The presentation, management, and outcome of a 37-year-old man with a right-sided IAC ALM are described., Results: Of 68 unique entries, 27 studies were included. Thirty-four cases of skull base LM (n = 6) or ALM (n = 28) were identified. Average age at presentation was 45.1 ± 14.5 years, and 52.9% of patients were male. Tumor diameter was 2.75 ± 1.6 cm, with headaches being the most reported symptom. Commonly reported locations were the cavernous sinus and the external auditory canal. Only 3 cases of IAC ALM met the criteria for this review. All tumors were treated with surgery, and gross total resection was achieved in 27 patients. Radiation was given in 3 cases with subtotal resection., Conclusions: Skull base LM and ALM are rare. Given the need for pathology, surgery has been the standard treatment for symptomatic skull base LM and ALM. It is important to understand the available data about this disease and consider it in the differential of skull base lesions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common problem during the postoperative course after pituitary surgery. Although treatment of this condition is well characterized, prevention strategies are less studied and reported. The authors sought to characterize outcomes and predictive factors of SIADH after implementation of routine postoperative fluid restriction for patients undergoing endoscopic transsphenoidal surgery for pituitary adenoma., Methods: In March 2018, routine postoperative fluid restriction to 1000 ml/day for 7 days was instituted for all patients who underwent surgery for pituitary adenoma. These patients were compared with patients who underwent surgery for pituitary adenoma between March 2016 and March 2018, prior to implementation of routine fluid restriction. Patients with preoperative history of diabetes insipidus (DI) or concern for postsurgical DI were excluded. Patients were followed by neuroendocrinologists and neurosurgeons, and sodium levels were checked between 7 and 10 days postoperatively. SIADH was defined by a serum sodium level less than 136 mmol/L, with or without symptoms within 10 days after surgery. Thirty-day readmission was recorded and reviewed to determine underlying reasons., Results: In total, 82 patients in the fluid-unrestricted cohort and 135 patients in the fluid-restricted cohort were analyzed. The patients in the fluid-restricted cohort had a significantly lower rate of postoperative SIADH than patients in the fluid-unrestricted cohort (5% vs 15%, adjusted OR [95% CI] 0.1 [0.0-0.6], p = 0.01). Higher BMI was associated with lower rate of postoperative SIADH (adjusted OR [95%] 0.9 [0.9-1.0], p = 0.03), whereas female sex was associated with higher rate of SIADH (adjusted OR [95% CI] 3.1 [1.1-9.8], p = 0.03). There was no difference in the 30-day readmission rates between patients in the fluid-unrestricted and fluid-restricted cohorts (4% vs 7%, adjusted OR [95% CI] 0.5 [0-5.1], p = 0.56). Thirty-day readmission was more likely for patients with history of hypertension (adjusted OR [95% CI] 5.7 [1.3-26.3], p = 0.02) and less likely for White patients (adjusted OR [95% CI] 0.3 [0.1-0.9], p = 0.04)., Conclusions: Routine fluid restriction reduced the rate of SIADH in patients who underwent surgery for pituitary adenoma but was not associated with reduction in 30-day readmission rate.

Background: Proximal junctional kyphosis (PJK) is a common postoperative complication after adult spinal deformity (ASD) surgery and may manifest with neurological decline, worsening spinal deformity, and spinal instability, which warrant reoperation. Rates of PJK may be as high as 69.4% after ASD surgery., Objective: To evaluate the efficacy of junctional tethers for PJK prophylaxis after multilevel instrumented surgery for ASD with minimum 2-yr follow-up., Methods: Single-center retrospective analysis of adult patients (age ≥18 yr) who underwent ASD surgery with index operations performed between November 2010 and June 2016 and achieved minimum 2-yr follow-up. Patients with ASD were subdivided into 3 treatment cohorts based on institutional protocol: no tether (NT), polyethylene tether-only (TO), and tether with crosslink (TC). PJK was defined as a proximal junctional angle (PJA) >10° and 10° greater than the corresponding preoperative measurement. Patient demographics, operative details, standard radiographic scoliosis measurements (including PJA and assessment of PJK), and complications were analyzed., Results: Of 184 patients, 146 (79.3%) achieved minimum 2-yr follow-up (mean = 45 mo; mean age = 67 yr; 67.8% women). PJK rates reported for the NT, TO, and TC cohorts were 60.7% (37/61), 35.7% (15/42), and 23.3% (10/43), respectively. PJK rates among TC patients were significantly lower than NT (P = .01601)., Conclusion: Junctional tethers with crosslink significantly reduced the incidence of PJK and revisions for PJK among ASD patients treated with long-segment posterior instrumented fusions who achieved minimum 2-yr follow-up., (© Congress of Neurological Surgeons 2021.)

Objective: Primary spinal meningiomas represent a rare indolent neoplasm usually situated in the intradural-extramedullary compartment. They have a predilection for afflicting the thoracic spine and most frequently present with sensory and/or motor symptoms. Resection is the first-line treatment for symptomatic tumors, whereas other clinical factors will determine the need for adjuvant therapy. In this study, the authors aimed to elucidate clinical presentation, functional outcomes, and long-term outcomes in this population in order to better equip clinicians with the tools to counsel their patients., Methods: This is a retrospective analysis of patients treated at the authors' institution between 1998 and 2018. All patients with thoracic meningiomas who underwent resection and completed at least one follow-up appointment were included. Multiple preoperative clinical variables, hospitalization details, and long-term outcomes were collected for the cohort., Results: Forty-six patients who underwent resection for thoracic meningiomas were included. The average age of the cohort was 59 years, and the median follow-up was 53 months. Persistent sensory and motor symptoms were present in 29 patients (63%). Fifteen lesions were ventrally positioned. There were 43 WHO grade I tumors, 2 WHO grade II tumors, and 1 WHO grade III tumor; the grade III tumor was the only case of recurrence. The median length of hospitalization was 4 days. Seventeen patients (37%) were discharged to rehabilitation facilities. Thirty patients (65.2%) experienced resolution or improvement of symptoms, and there were no deaths within 30 days of surgery. Only 1 patient developed painful kyphosis and was managed medically. Ventral tumor position, new postoperative deficits, and length of stay did not correlate with disposition to a facility. Age, ventral position, blood loss, and increasing WHO grade did not correlate with length of stay., Conclusions: Outcomes are overall favorable for patients who undergo resection of thoracic meningiomas. Symptomatic patients often experience improvement, and patients generally do not require significant future operations. Tumors located ventrally, while anatomically challenging, do not necessarily herald a significantly worse prognosis or limit the extent of resection.

Objective: Early surgical intervention for patients with pituitary apoplexy (PA) is thought to improve visual outcomes and decrease mortality. However, some patients may have good clinical outcomes without surgery. The authors sought to compare the radiological and clinical outcomes of patients with PA who were managed conservatively versus those who underwent early surgery., Methods: Patients with symptomatic PA were identified. Radiological, endocrinological, and ophthalmological data were reviewed. Patients with progressive visual deterioration or ophthalmoplegia were candidates for early surgery (within 7 days). Patients without visual symptoms or whose symptoms improved on high-dose steroids were treated conservatively. Log-rank and univariate analysis compared clinical and radiological outcomes between those receiving early surgery and those who underwent intended conservative management., Results: Sixty-four patients with PA were identified: 47 (73.4%) underwent intended conservative management, while 17 (26.6%) had early surgery. Patients receiving early surgery had increased rates of impaired visual acuity (VA; 64.7% vs 27.7%, p = 0.009); visual field (VF) deficits (64.7% vs 19.2%, p = 0.002); and cranial neuropathies (58.8% vs 29.8%, p < 0.05) at presentation. Tumor volumes were greater in the early surgical cohort (15.1 ± 14.8 cm3 vs 4.5 ± 10.3 cm3, p < 0.001). The median clinical and radiological follow-up visits were longer in the early surgical cohort (70.0 and 64.4 months vs 26.0 and 24.7 months, respectively; p < 0.001). Among those with VA/VF deficits, visual outcomes were similar between both groups (p > 0.9). The median time to VA improvement (2.0 vs 3.0 months, p = 0.9; HR 0.9, 95% CI 0.3-3.5) and the median time to VF improvement (2.0 vs 1.5 months; HR 0.8, 95% CI 0.3-2.6, p = 0.8) were similar across both cohorts. Cranial neuropathy improvement was more common in conservatively managed patients (HR 4.8, 95% CI 1.5-15.4, p < 0.01). Conservative management failed in 7 patients (14.9%) and required surgery. PA volumes spontaneously regressed in 95.0% of patients (38/40) with successful conservative management, with a 6-month regression rate of 66.2%. Twenty-seven patients (19 in the conservative and 8 in the early surgical cohorts) responded to a prospectively administered Visual Function Questionnaire-25 (VFQ-25). VFQ-25 scores were similar across both cohorts (conservative 95.5 ± 3.8, surgery 93.2 ± 5.1, p = 0.3). Younger age, female sex, and patients with VF deficits or chiasmal compression were more likely to experience unsuccessful conservative management. Surgical outcomes were similar for patients receiving early versus delayed surgery., Conclusions: These data suggest that a majority of patients with PA can be successfully managed without surgical intervention assuming close neurosurgical, radiological, and ophthalmological follow-up is available.

Neurofibromatosis type 2 (NF2) is a rare, hereditary tumor syndrome, often requiring repeated surgeries for multiple lesions with significant cumulative morbidity. As such, non-operative management should be considered when possible for this patient population. The aim of this study is to provide a systematic review of the literature regarding this treatment strategy. A descriptive case of a patient in whom bevacizumab treatments enabled over 15 years of surgical postponement for a symptomatic spinal cord ependymoma is also provided. Evidence suggests that bevacizumab is a reasonable surgery-deferring option for cystic lesions, and it may be especially useful in NF2 patients to reduce cumulative morbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pancreatoblastoma is an extremely rare neoplasm that accounts for 0.5% of all pancreatic exocrine tumors. These rare entities typically manifest in the pediatric population but can rarely occur in adults. Systemic seeding has been described before but intracranial metastasis in adults has yet to be described., Case Description: A 28-year-old woman with a history of pancreatoblastoma that had been in remission for 51 months after treatment with cisplatin, doxorubicin (Adriamycin), and etoposide had presented to the emergency room with chronic recurrent headaches. Conservative management of the headaches failed, which led to a diagnostic workup with magnetic resonance imaging of the brain. Magnetic resonance imaging demonstrated a well-circumscribed solitary cerebellar lesion. Metastatic disease was suspected, and the patient underwent suboccipital craniotomy for tumor resection with adjuvant gamma knife radiosurgery., Conclusions: Central nervous system seeding of pancreatoblastoma is rare, and the available evidence suggests that the strategy we used could be adequate for treating such occurrences., (Published by Elsevier Inc.)

Background: Although extraparenchymal neurocysticercosis (NCC) is well established, presentation in the suprasellar space is rare. When presenting in the suprasellar space, the imaging characteristics may mimic more common lesions including craniopharyngioma and Rathke cleft cyst depending on the life cycle of the parasite. Although antiparasitic medical therapy may be effective for viable NCC, it is not routinely employed for calcified NCC., Case Description: This report presents a 39-year-old male patient who presented with profound visual decline secondary to a partially calcified suprasellar NCC. Suprasellar NCC was presumed based on specific radiologic findings, which are discussed. Medical therapy was not offered because of the proximity to the optic chiasm and the partial calcification of the lesion leading to the presumption that the mass was nonviable. The patient underwent successful endoscopic endonasal resection of the suprasellar NCC and experienced significant improvement in vision. Despite the calcification, pathological evaluation revealed that a portion remained viable., Conclusions: Regardless of the life cycle stage, endonasal resection offers a minimally invasive approach for suprasellar NCC; treatment can be tailored to the patient's presentation and stage of infection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To analyze the association between dosvolume relationships and adverse events in brainstem lesions treated with Gamma Knife radiosurgery (GKRS)., Methods: Treatment plans were generated on BrainLab Elements and GammaPlan software. Dosimetric data were analyzed as continuous variables for patients who received GKRS to brain metastases or arteriovenous malformations (AVM) within or abutting the brainstem. Adverse events were classified as clinical and/or radiographic. Logistic and cox regression were used to assess the relationship between dosimetric variables and adverse events., Results: Sixty-one patients who underwent single fraction GKRS for brain metastases or AVM were retrospectively analyzed. Median age was 62 years (range: 12-92 years) and the median prescription dose was 18 Gy (range: 13-25 Gy). Median follow-up was 6months. Clinical and radiographic complications were seen in ten (16.4%) and 17 (27.9%) patients, respectively. On logistic regression, increasing D 05% was found to be associated with an increased probability of developing a clinical complication post-GKRS (OR: 1.18; 95% CI: 1.01-1.39; p = 0.04). Furthermore, mean brainstem dose (HR: 1.43; 95% CI: 1.05-1.94; p < 0.02), D 05% (HR: 1.09; 95% CI: 1.01-1.18; p = 0.03), and D 95% (HR: 2.37; 95% CI: 0.99-5.67; p = 0.05) were associated with an increased hazard of experiencing post-GKRS complications over time., Conclusions: Increasing D 05% to the brainstem is associated with an increased risk of developing clinical complications. Clinicians may consider this parameter in addition to fractionated stereotactic radiation therapy when well-established dose constraints are not met in this patient population. Additional data are needed to further validate these findings., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Crooke cell adenoma is a very rare subtype of pituitary neoplasm that is known to be clinically aggressive. These tumors can secrete adrenocorticotropic hormone or may be endocrinologically silent. We evaluated the effect of Gamma Knife radiosurgery (GKRS) on endocrine remission and tumor control., Materials and Methods: This study comprised 5 patients (2 men, 3 women; median age at GKRS, 55 years [range, 21-65 years]) with pathology-confirmed Crooke cell adenoma treated with GKRS at the Gamma Knife Center of the University of Virginia. The median time interval between transsphenoidal resection and GKRS was 5.8 months. The median margin dose was 25 Gy (range, 18-25 Gy). Median treated adenoma volume was 3.12 mL. Median follow-up was 107 months (range, 44-122 months)., Results: Tumor control was achieved in all patients. Three patients achieved endocrine remission at the last follow-up. The median time interval to cortisol normalization when off of anti-hormone secreting medication was 12 months (range, 6-24 months). Newly developed or worsening endocrinopathy occurred in 3 patients at 6, 15, and 18 months, respectively. Cranial nerve III neuropathy developed in 1 patient. Two patients required bilateral adrenalectomy at 44 months and 50 months, respectively, following GKRS., Conclusions: GKRS appears to be a safe and reasonably effective treatment option for Crooke cell adenoma. Multicenter studies with larger numbers of patients are needed to verify these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Some patients are diagnosed with asymptomatic meningioma(s) after undergoing a screening CT and MRI for minor ailments or postresection., Objective: To help clinicians in decision making for treatment of asymptomatic meningiomas., Methods: A single center retrospective cohort study of 117 patients with 122 tumors treated with Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden). Patients were followed with longitudinal imaging and clinical evaluations. Tumor volumetry and developments of new signs or symptoms after GKRS were the end points in the study., Results: Median patient age at GKRS was 60 yr (range 21-86 yr) with a median clinical follow-up of 53 mo (range 20-252 mo). The median pre-GKRS tumor volume was 3.6 ± 3.8 cc (±standard deviation). Tumors were treated with a median margin dose of 14 ± 2 Gy. At last follow-up, median tumor volume was 2.5 ± 3.6 cc. Radiological progression-free survival (PFS) rates were 97% and 94.4% at 5 yr and 10 yr, respectively. Clinical PFS rates were 86% and 70% at 5 yr and 10 yr, respectively. Development of neurological complications was seen in 21 (18%) patients, and 11 (52%) of them had undergone surgical resection prior to GKRS., Conclusion: GKRS is a reasonable treatment strategy for asymptomatic meningiomas and compares favorably to natural history studies in terms of tumor control and neurological preservation. It results in relatively low morbidity in previously untreated meningiomas and serves as an appealing alternative treatment modality for recurrent meningiomas in asymptomatic patients., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Pyoderma gangrenosum (PG) is a rare inflammatory dermatosis that is most often associated with inflammatory bowel disease, but which can occur as a pathergic reaction around surgical incisions. The authors report the case of a patient who developed postoperative PG over the course of several months after undergoing extensive spinal instrumentation between the T4 and iliac levels. This is only the second such case occurring after spine surgery to be reported. The authors additionally review the literature to characterize treatment approaches and outcomes for this condition. The case highlights a potentially severe adverse effect of surgery that can be difficult to recognize and causes delays in effective treatment. It also demonstrates the importance of multidisciplinary collaboration in the effective care of patients.

Objective: To assess outcomes and complications of stereotactic radiosurgery treatment for trigeminal schwannoma (TS)., Methods: A retrospective analysis was performed to describe the presentation and outcomes of patients undergoing Gamma Knife radiosurgery (GKRS) for TS. Clinical, radiographic, and stereotactic radiosurgery dose plans were reviewed. Descriptive statistics and univariate analysis were performed to identify factors associated with poor tumor control., Results: A total of 22 patients with TS were treated with GKRS between 1990 and 2018. One patient had a history of neurofibromatosis type II. Of the study population, 81% underwent GKRS as a first-line treatment. The average tumor volume was 3.3 cm 3 and the average margin treatment dose was 14.1 Gy. The median clinical and radiographic follow-up period were 18.5 and 27 months, respectively. Tumor control was achieved in 17 patients (77.3%). Symptomatic improvement was noted in 8 patients (42.1%). Tumor expansion was observed in 7 patients (31.8%) and was associated with poor tumor control at last follow-up (P < 0.05). Patients who developed transient tumor expansion had higher margin doses (14.9 ± 1.1 Gy) compared with patients who did not have expansion (13.6 ± 1.3 Gyk P < 0.05)., Conclusions: GKRS provides effective control for most TS. Increased margin doses are associated with tumor expansion, which was a poor prognostic event associated with progression and clinical decline. Based on these results, combined with analysis of available data from other series of TS treated with GKRS, we believe that margin dose between 13 and 14 Gy offers a high probability of tumor control, yet minimizing risk of adverse radiation effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Training is a critical part of health information technology implementations, but little emphasis is placed on post-implementation training to support day-to-day activities. The goal of this study was to evaluate the impact of post-implementation training on key electronic health record activities., Methods: Based on feedback from providers and requests for technical support, we developed two classes designed to improve providers' effectiveness with the electronic health record. Training took place at Kaiser Permanente, Mid-Atlantic States. The classes focused on managing patient-level information using problem lists and medication lists, as well as efficient documentation and chart review. Both classes used the blended learning method, integrating concrete scenarios, hands-on exercises and take-home materials to reinforce class concepts. To evaluate training effectiveness, we used a case-control study with a 1:4 match on pre-training performance. We measured the usage rate of two key electronic health record functions (problem list and medication list management) for six months before and after training. Change scores were compared using the Wilcoxon sign rank test., Results: 36 participants and 144 non-participants were included in the training evaluation. Training participants were more likely to manage both medication lists and problem lists after training. Class material is now being incorporated into an enterprise-wide multi-modal training program available to all providers at Kaiser Permanente in the Mid-Atlantic States., Conclusions: Ongoing information technology training is well-received by healthcare providers, who expressed a clear preference for additional training. Training improved use of two important electronic health record features that are included as part of the Meaningful Use criteria.

Objective: To determine whether office-based interventions change adolescents' alcohol beliefs and alcohol use., Design: Randomized, controlled trial., Setting: Five managed care group practices in Washington, DC., Participants: Consecutive 12- to 17-year-olds (N = 409) seeing primary care providers (N = 26) for general check-ups. Most of the adolescents (79%) were African American, 44% were male, and 16% currently drank., Interventions: Usual care (Group I), adolescent priming with alcohol self-assessment just prior to check-up (Group II), adolescent priming and provider prompting with adolescent self-assessment and brochure (Group III)., Main Outcome Measures: Adolescent alcohol beliefs at exit interview and self-reported behaviors at 6- and 12-month follow-up., Results: At exit interview, Groups II and III reported that less alcohol was needed for impaired thinking and a greater intent to drink alcohol in the next 3 months than Group I. At 6 months, Group III reported more resistance to peer pressure to drink, and Groups II and III reported more bingeing than Group I. At 1-year follow-up, controlling for baseline levels, Groups II (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.44-6.24) and III (OR, 2.86; CI, 1.13-7.26) reported more bingeing in the last 3 months than Group I. Group II reported more drinking in the last 30 days (OR, 2.31; CI, 1.31-4.07) and in the last 3 months (OR, 1.76; CI, 1.12-2.77) than Group I., Conclusion: Brief office-based interventions were ineffective in reducing adolescent alcohol use but may increase adolescent reporting of alcohol use.

Objectives: To assess differences in provider willingness to screen all sexually active male and female adolescents for chlamydia and to determine whether concerns about cost effectiveness of screening are related to provider willingness to screen for chlamydia., Methods: All primary care providers in a managed care organisation self administered a survey about screening all sexually active adolescents for chlamydia., Results: Respondents were 217 physicians (MDs) and 121 nurse practitioners (NPs) or physician assistants (PAs). Excluding obstetrician/gynaecologists, more providers were willing to routinely screen adolescent females than males for chlamydia (67% v 49% respectively; p<0.001). Independent predictors of provider willingness to screen both males and females included belief that routine screening is cost effective and being a NP/PA v an MD. Belief that chlamydia screening is easier in females than males independently predicted less willingness to screen males., Conclusion: Information that reduces provider concern about the cost effectiveness of screening may increase provider willingness to screen adolescents for chlamydia. Availability of urine based tests may reduce provider beliefs that females are easier to screen than males and increase chlamydia screening in males.

Goal: To determine chlamydia screening practices and the resulting positive test results for adolescents enrolled in a large nonprofit managed care organization., Study Design: The electronic medical records of all 12- to 19-year-olds enrolled in a large nonprofit managed care organization serving a demographically diverse patient population from January 1998 through December 1999 were reviewed retrospectively., Results: Among the 43,205 female and 44,133 male managed care organization members, ages 12 to 19 years in 1998-1999, 7575 adolescents (8.7%) (6914 females [16%] and 661 males [1.5%]) were tested for chlamydia. Among the members tested, chlamydia was diagnosed in 1109 adolescents (14.6%) (983 females [14.2] and 126 males [19.1%]); 761 (68.6%) adolescents were retested for chlamydia; and 182 (16.4%) had repeat positive test results. The median time to diagnosis of a repeat infection was 6 months., Conclusions: Chlamydia imposes a large disease burden in the private, organized healthcare sector. Managed care organizations can use operational data to enhance chlamydia prevention services by defining testing practices and local disease prevalence.

A cold-adapted (ca) influenza B reassortant that derived two genes encoding the hemagglutinin and neuraminidase from influenza B/Ann Arbor/1/86 wild-type virus and six internal RNA segments from ca influenza B/Ann Arbor/1/66 virus was evaluated in 66 adult volunteers having a serum hemagglutination inhibition antibody titer less than or equal to 1:8. The ca reassortant was attenuated and elicited the production of systemic and local antibodies; the 50% human infectious dose was 10(6.4) TCID50. Six weeks after vaccination, 12 unvaccinated volunteers and 13 recipients of ca virus (10(7.5) TCID50) were challenged experimentally with homologous wild-type influenza B virus. The ca vaccine completely protected against illness, and the magnitude of shedding was 50-fold less in vaccinees than in unimmunized controls, five of whom became ill. These findings indicate that the six internal RNA segments of the ca influenza B/Ann Arbor/66 donor virus confer desirable properties of a live virus vaccine to a reassortant derived from a virulent virus. Such reassortants may be suitable vaccines for healthy adults.

Previously a spontaneous 36 nucleotide deletion in the coding region of NS1 was detected in the NS gene of a reassortant virus (CR43-3) recovered from a dual infection by the influenza A/Ann Arbor/6/60 cold-adapted (ca) mutant and wild-type (wt) influenza A/Alaska/6/77 (H3N2). The hemagglutinin, neuraminidase and NS genes were derived from the wild type virus parent while the other 5 genes were derived from the ca parent. The CR43-3 reassortant virus exhibited: (i) a host range (hr) phenotype, i.e. the reassortant replicated efficiently in avian cells in tissue culture but failed to grow in mammalian (MDCK) cell culture and (ii) an attenuation (att) phenotype, i.e., the reassortant was restricted in replication in the upper and lower respiratory tract of ferrets and hamsters. Since the CR43-3 reassortant possessed 5 genes from the ca parent which are each known to contain one or more mutations, it was not possible to assign the hr and att phenotypes solely to the NS deletion mutant gene. In order to determine the phenotype(s) specified solely by the mutant NS gene, it was transferred into a reassortant virus (143-1) which derived its seven other genes from the homologous wild type A/Alaska/6/77 virus. The deletion mutant NS gene specified only a partial hr phenotype manifested by a reduction in plaque size in MDCK tissue, but not a reduction in plaque number. Thus, the complete hr manifested by the CR43-3 parent virus is specified by the mutant NS1 gene acting in concert with one or more genes derived from the ca virus. The clone 143-1 virus exhibited the ts phenotype and was restricted in plaque formation at 37 degrees C in MDCK cells, a level of temperature sensitivity previously shown with other ts mutants to correlate with significant restriction of viral replication in the lower respiratory tract of hamsters. However, the clone 143-1 virus grew almost as well as the wt virus in the upper and lower respiratory tracts of hamsters and chimpanzees and thus did not possess the att phenotype. The finding that the ts phenotype was not manifest in vivo in animals with a 37 degrees C core temperature indicates that the mutated NS1 gene specifies a host dependent ts phenotype with replication restricted in vitro (MDCK tissue culture) at 37 degrees C but not in vivo in the lungs of hamsters and chimpanzees. ts+ virus was readily recovered from infected hamsters and chimpanzees indicating that the ts phenotype specified by the 36-base deletion was not stable following replication in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

A reassortant influenza A virus was produced by mating an avian influenza A/Pintail/Alberta/119/79 (H4N6) virus with wild-type human influenza A/Washington/897/80 (H3N2) virus. The avian-human influenza A reassortant virus contained the genes coding for the hemagglutinin and neuraminidase surface antigens of the human influenza wild-type virus and the six other RNA segments (internal genes) of the avian influenza A virus donor. In the lower respiratory tract of squirrel monkeys, this avian-human influenza reassortant virus, like its avian influenza A parent virus, was restricted approximately 100-fold in replication compared with the wild-type human influenza A virus. Despite this restriction of replication, infection of monkeys with the avian-human influenza A reassortant virus induced resistance to wild-type human influenza A virus challenge. In comparison with the wild-type human influenza A virus, the avian-human influenza A reassortant was also fully attenuated when 10(5.5) to 10(7.5) 50% tissue culture infective doses were administered to susceptible adult volunteers. Attenuation was indicated by a more than 300-fold reduction in virus shedding and lack of reactogenicity. The reassortant virus did not spread to susceptible contacts and could not be isolated from the blood or stools of infected adults. The 50% human infectious dose was 10(6.2) 50% tissue culture infective dose, indicating that this reassortant virus is only slightly less infectious for adults than a similarly derived avian-human influenza A/Washington/80 X A/Mallard/78 reassortant virus. These findings suggest that the avian influenza A/Pintail/79 virus may be a satisfactory donor of attenuating genes for production of live, attenuated avian-human influenza A reassortant virus vaccines.

The serum antibody response of 50 infants and children infected with respiratory syncytial virus (RSV) was determined by a glycoprotein-specific enzyme-linked immunosorbent assay, and the effects of age and preexisting antibody titer at the time of RSV infection on response to the G and F glycoproteins of RSV were examined. The immune response to the G and F glycoproteins was assessed with anti-human immunoglobulin A to permit measurement of the response of young infants in the presence of maternally derived immunoglobulin G. The findings suggested that age primarily affects the response to the F glycoprotein and that preexisting antibody titer affects the response to the G glycoprotein.

The infectivity, immunogenicity, and efficacy of live, attenuated influenza A/Texas/1/85 (H1N1) and A/Bethesda/1/85 (H3N2) avian-human (ah) and cold-adapted (ca) reassortant vaccines were compared in 252 seronegative adult volunteers. The immunogenicity and efficacy of the H1N1 reassortant vaccine were also compared with those of the trivalent inactivated virus vaccine. Each reassortant vaccine was satisfactorily attenuated. The 50% human infectious dose was 10(4.9) for ca H1N1, 10(5.4) for ah H1N1, 10(6.4) for ca H3N2, and 10(6.5) TCID50 for ah H3N2 reassortant virus. Within a subtype, the immunogenicities of ah and ca vaccines were comparable. Five to seven weeks after vaccination, volunteers were challenged with homologous wild-type influenza A virus. The magnitude of shedding of virus after challenge was greater than 100-fold less in H1N1 vaccinees and greater than 10-fold less in H3N2 vaccinees compared with unimmunized controls. The vaccines were equally efficacious, as indicated by an 86%-100% reduction in illness. Thus, the ah A/Mallard/New York/6750/78 and the ca A/Ann Arbor/6/60 reassortant viruses are comparable.

We compared the abilities of the six internal RNA segments of two avian influenza viruses, A/Mallard/Alberta/88/76 (H3N8) and A/Mallard/NY/6750/78 (H2N2), to confer attenuation on wild-type human influenza A/Bethesda/1/85 (H3N2) virus in seronegative adult volunteers. Live avian-human influenza A reassortant virus vaccines derived from either avian virus parent were comparable in the following properties: safety, infectivity, immunogenicity, and genetic stability. Since the avian influenza A/Mallard/Alberta/76 virus offered no clear advantage as a donor virus, we will conduct our future evaluations on live influenza A virus reassortants derived from the more extensively characterized avian influenza A/Mallard/NY/78 virus.

Serum samples from 31 children who experienced two or three infections with respiratory syncytial virus (RSV) in the first four years of life were tested in an enzyme-linked immunosorbent assay to examine the immunoglobulin G (IgG) subclass responses to the RSV F and G surface glycoproteins associated with primary infection and reinfection. We sought to determine whether the greater degree of glycosylation of the G glycoprotein was reflected in an IgG subclass immune response more like that to a polysaccharide antigen than to a protein antigen. We found that the IgG1/IgG2 ratio of postinfection antibody titers to F was fourfold higher than that to the G glycoprotein after RSV infections 1, 2, and 3. The IgG2 response to the heavily glycosylated G glycoprotein differed from that to a polysaccharide antigen in that the IgG1/IgG2 ratio remained constant with age, whereas the response to a polysaccharide antigen decreased as the IgG2 response increased with age. We also noted that antibody responses to both surface glycoproteins in the IgG1 and IgG2 subclasses reached their maximum levels after RSV infection 2.

The mitotic selection procedure for cell cycle analysis was utilized to investigate the concentration-dependent modification of radiation-induced division delay in Chinese hamster ovary (CHO) cells by methyl xanthines (caffeine, theophylline, and theobromine) and by dibutyryl cyclic AMP. The methyl xanthines (concentrations from 0.5 to 1000 micrograms/ml) all reduced radiation-induced division delay with the effect being linear between approximately 100 and 1000 micrograms/ml. After doses of 100-300 rad, delay was reduced by 75, 94 or 83 per cent at 1000 micrograms/ml for each drug, respectively. However, the addition of dibutyryl cyclic AMP had an opposite effect: radiation-induced delay was increased by the concentration range of 0.3 to 300 micrograms/ml. These results indicate that in mammalian cells the control of cell cycle progression and the modification of radiation-induced division delay are not simply related to intracellular levels of cyclic AMP. Rather, there appear to be at least two competing mechanisms which are differentially affected by caffeine analogues or by direct addition of dibutyryl cyclic AMP. The direct effect of caffeine and the methyl xanthines on membrane calcium permeability is considered.

Clinical studies previously demonstrated that live influenza A virus vaccines derived by genetic reassortment from the mating of influenza A/Ann Arbor/6/60 (H2N2) cold-adapted (ca) donor virus with epidemic wild-type influenza A viruses are reproducibly safe, infectious, immunogenic, and efficacious in the prevention of illness caused by challenge with virulent wild-type virus. These influenza A reassortant virus vaccines also express the ca and temperature sensitivity (ts) phenotypes in vitro, but the genes of the ca virus parent which specify the ca, ts, and attenuation (att) phenotypes have not adequately been defined. To identify the genes associated with each of these phenotypes, we isolated six single-gene substitution reassortant viruses, each of which inherited only one RNA segment from the ca parent virus and the remaining seven RNA segments from the A/Korea/1/82 (H3N2) wild-type virus parent. These were evaluated in vitro for their ca and ts phenotypes and in ferrets, hamsters, and seronegative adult volunteers for the att phenotype. We found that the polymerase PA gene of the ca parent specifies the ca phenotype and that the PB2 and PB1 genes independently specify the ts phenotype. The PA, M, PB2, and PB1 genes of the ca donor virus each contribute to the att phenotype. The finding that four genes of the ca donor virus contribute to the att phenotype provides a partial explanation for the observed phenotypic stability of ca reassortant viruses following replication in humans.

We evaluated the abilities of three different avian influenza A viruses to attenuate the wild-type human influenza A/Korea/1/82 (H3N2) virus in squirrel monkeys, chimpanzees, and adult seronegative human volunteers. Two of these, avian influenza A/Mallard/NY/78 and A/Mallard/Alberta/76 viruses, appeared to be satisfactory donors of attenuating genes for the production of live influenza A reassortant virus vaccines for human use because the reassortants exhibited an acceptable balance between attenuation and immunogenicity.

Wild-type influenza A viruses can be attenuated for humans by the acquisition of genes from the A/Ann Arbor/6/60 cold-adapted (ca) donor virus. Six-gene reassortants, that is, viruses containing the hemagglutinin and neuraminidase surface glycoprotein genes of the wild-type virus and the six remaining RNA segments of the ca donor virus, are consistently attenuated for humans. During the production of a six-gene reassortant virus containing the surface glycoproteins of the A/Washington/897/80 (H3N2) wild-type virus, a reassortant virus was isolated that contained RNA segments 3 (coding for the polymerase PA protein) and 7 (coding for matrix [M] proteins) from the ca parent and all other genes from the wild-type virus. This reassortant virus is referred to as a two-gene reassortant. Because the gene or set of genes responsible for the attenuation of ca reassortant viruses has not been defined, we evaluated the two-gene reassortant for level of replication and level of virulence in ferrets and in humans, and we compared its characteristics to those of a six-gene reassortant virus derived from the same two parents. The two-gene reassortant virus infected each of 14 adult seronegative (serum hemagglutination inhibition titer of less than or equal to 1:8) volunteers when administered intranasally at a dose of 10(7) 50% tissue culture infectious doses, yet it did not produce illness. The level of replication of the two-gene reassortant virus in the upper respiratory tract was equivalent to that of the six-gene reassortant virus. This demonstrates that transfer of the A/Ann Arbor/6/60 ca PA polymerase and M genes is sufficient to confer the attenuation phenotype on wild-type influenza A viruses. In the context of previous observations, these results suggest that the A/Ann Arbor/6/60 ca donor virus PA polymerase gene plays a major role in the attenuation of ca reassortant viruses.

The temperature sensitivity, level of attenuation, and phenotypic stability of an influenza B/Texas/1/84 X B/Ann Arbor/1/66 cold-adapted (ca) reassortant virus that received the RNA segments that encode the hemagglutinin and neuraminidase surface glycoproteins from the B/Texas/84 wild-type virus and the remaining six RNA segments from the B/Ann Arbor/66 ca donor virus were evaluated. In comparison to wild-type virus, the ca reassortant was restricted in replication in the upper and lower respiratory tracts of hamsters and chimpanzees. This clearly demonstrated that the six transferable RNA segments of the B/Ann Arbor/66 ca donor virus specify the attenuation phenotype for animals with a 37 degrees C core body temperature. In addition, the ca virus retained the temperature-sensitive (ts) phenotype after replication in hamsters and chimpanzees. To further evaluate its phenotypic stability, the ca reassortant virus was isolated after 6-15 d of replication in hamsters that were immunosuppressed with cyclophosphamide, and the isolates were tested for their temperature sensitivity in vitro and for their level of replication in immunocompetent hamsters. The isolated viruses retained their ts and attenuation phenotypes even after prolonged replication in vivo. Thus, the B/Ann Arbor/66 ca donor virus can transfer the desired properties of attenuation and phenotype stability to its reassortants. The findings support the continued evaluation of ca reassortant influenza B virus vaccines in humans, including fully susceptible children.