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Axoplasmic transport is a dramatic example of cytoplasmic motility. Constituents of axoplasm migrate as far as 400 mm/d or at approximately 5 micron/s. Thin-section studies have identified the major morphological elements within the axoplasm as being microtubules, neurofilaments (100-A filaments), an interconnected and elongated varicose component of smooth endoplasmic reticulum (SER), more dilated and vesicular organelles resembling portions of SER, multivesicular bodies, mitochondria, and, finally, a matrix of ground substance in which the tubules, filaments, and vesicles are suspended. In the ordinary thin-section image, the ground substance is comprised of wispy fragments which, in not being noticeably tied together, do not give the impression of representing more than a condensation of what might be a homogeneous solution of proteins. With the high-voltage microscope on thick (0.5-micron) sections, we have noticed, however, that the so-called wispy fragments are part of a three-dimensional lattice. We contend that this lattice is not an artifact of aldehyde fixation, and our contention is supported by its visability after rapid-freezing and freeze-substitution. This lattice or microtrabecular matrix of axoplasm was found to consist of an organized system of cross-bridges between microtubules, neurofilaments, cisternae of the SER, and the plasma membrane. We propose that formation and deformation of this system are involved in rapid axonal transport. To facilitate electron microscope visualization of the trabecular connections between elements of axoplasm, the following three techniques were used: first, the addition of tannic acid to the primary fixative, OsO4 postfixation, then en bloc staining in uranyl acetate for conventional transmission electron microscope (TEM); second, embedding tissue in polyethylene glycol for thin sectioning, dissolving out the embedding medium from the sections and blocks, critical-point-drying (J. J. Wolosewick, 1980, J. Cell Biol., 86:675-681.), and then observing the matrix-free sections with TEM or the blocks with a scanning electron microscope; and third, rapid freezing of fixed tissue followed by freeze-etching and rotary-shadowing with replicas observed by TEM. All of these procedures yielded images of cross-linking elements between neurofilaments and organelles of the axoplasm. These improvements in visualization should enable us to examine the distribution of trabecular links on motile axonal organelles.

Abstract Background Quality improvement (QI) programs focused on mastery of content by individual staff members are the current standard to improve resident outcomes in nursing homes. However, complexity science suggests that learning is a social process that occurs within the context of relationships and interactions among individuals. Thus, QI programs will not result in optimal changes in staff behavior unless the context for social learning is present. Accordingly, we developed CONNECT, an intervention to foster systematic use of management practices, which we propose will enhance effectiveness of a nursing home Falls QI program by strengthening the staff-to-staff interactions necessary for clinical problem-solving about complex problems such as falls. The study aims are to compare the impact of the CONNECT intervention, plus a falls reduction QI intervention (CONNECT + FALLS), to the falls reduction QI intervention alone (FALLS), on fall-related process measures, fall rates, and staff interaction measures. Methods/design Sixteen nursing homes will be randomized to one of two study arms, CONNECT + FALLS or FALLS alone. Subjects (staff and residents) are clustered within nursing homes because the intervention addresses social processes and thus must be delivered within the social context, rather than to individuals. Nursing homes randomized to CONNECT + FALLS will receive three months of CONNECT first, followed by three months of FALLS. Nursing homes randomized to FALLS alone receive three months of FALLs QI and are offered CONNECT after data collection is completed. Complexity science measures, which reflect staff perceptions of communication, safety climate, and care quality, will be collected from staff at baseline, three months after, and six months after baseline to evaluate immediate and sustained impacts. FALLS measures including quality indicators (process measures) and fall rates will be collected for the six months prior to baseline and the six months after the end of the intervention. Analysis will use a three-level mixed model. Discussion By focusing on improving local interactions, CONNECT is expected to maximize staff's ability to implement content learned in a falls QI program and integrate it into knowledge and action. Our previous pilot work shows that CONNECT is feasible, acceptable and appropriate. Trial Registration ClinicalTrials.gov: NCT00636675

COVID-19, caused by the SARS-CoV-2 virus, can lead to widespread neurological complications, including cognitive deficits and neurodegenerative symptoms, even in the absence of significant structural brain abnormalities. The potential neuroprotective effects of SARS-CoV-2 vaccination remain underexplored. Here, we demonstrate the neuroprotective effects of a psoralen-inactivated SARS-CoV-2 vaccine in a non-human primate model using resting-state magnetoencephalography (MEG), a non-invasive neurophysiological recording technique with sub-millisecond temporal and submillimeter spatial resolution. MEG scans demonstrated substantial preservation of neural activity across multiple brain regions in vaccinated subjects compared to unvaccinated controls following viral challenge. This approach not only underscores the role of vaccination in mitigating severe neurological outcomes but also highlights the capability of MEG to detect subtle yet significant changes in brain function that may be overlooked by other imaging modalities. These findings advance our understanding of vaccine-induced neuroprotection and establish MEG as a powerful tool for monitoring brain function in the context of viral infections.

Study Design: Retrospective observational study., Objective: To evaluate whether the combined American Spine Registry and Medicare (ASR/CMS) data yields substantially different findings versus ASR data alone with regard to key parameters such as risk stratification, complication rates and readmission rates in lumbar surgery investigated through an analysis of 8,755 spondylolisthesis cases., Summary of Background Data: Medicare data correlation has been effective for determining revision rates for other procedures such as total hip replacement. Our aim is to determine whether these findings are translatable in the realm of lumbar spinal surgery investigated through an analysis of 8,755 spondylolisthesis cases., Methods: The American Spine Registry (ASR) was queried for Medicare-eligible patients who underwent lumbar spinal fusion for lumbar spondylolisthesis. This cohort was analyzed based upon ASR data alone in comparison to the same patients in the combined ASR/Medicare (ASR/CMS) dataset. The primary outcome of interest was readmission at 30 and 90 days postoperatively., Results: There were 8,755 Medicare-eligible cases with a diagnosis of spondylolisthesis within the ASR. The mean age was 72.7 years, 60.8% were female. Medical comorbidities were more frequently detected in the combined ASR/CMS dataset, reflected by a higher mean Charlson Comorbidity Index score (3.49 vs. 3.27, P<0.001). Hospital readmission rates were significantly higher in the combined ASR/CMS dataset at both 30 days (4.89% vs. 1.83%, P<0.001) and 90 days (7.68% vs. 2.66%, P<0.001), with notable increases in readmissions for infections and medical complications. Discharge disposition remained comparable across datasets, with most patients discharged to home or home health care., Conclusion: This study demonstrates that integrating patient-identified Medicare data with the ASR provides a more comprehensive assessment of outcomes for lumbar spinal fusion surgery as demonstrated through an analysis of 8,755 spondylolisthesis cases. These findings, establish the importance of multi-source data linkage to overcome the limitations of single-source registries, thereby enhancing data quality for clinical decision-making and quality improvement in spinal surgery., Competing Interests: Conflicts of Interest/Funding Statement: Dr. Glassman is a consultant for Medtronic, Stryker, Proprio, K2M, and Depuy; has received royalties and has a patent with Medtronic; received research funding and support from Norton Healthcare, Pfizer,Texas Scottish Rite Hospital, Alan L. & Jacqueline B. Stuart Spine Research, Cerapedics, Inc., Scoliosis Research Society, Medtronic, National Spine Health Foundation, and Stryker. Dr. Djurasovic is a consultant for Medtronic, Globus, NuVasive; royalties from Medtronic, Globus, and NuVasive; and research support from Medtronic and Cerapedics. Dr. Asher reports royalties from Globus. Dr. Bydon is a consultant for AgNovos, Amgen and Medtronic. For the remaining authors none were declared., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Maternal morbidity and mortality rates in the United States have increased in the last two decades with a disproportionate impact on women of color. While numerous factors contribute to the inequities in pregnancy-related mortality, access to health insurance is among the most significant. Military Tricare models universal health care access; however, in studies looking at births in military treatment facilities, disparities still exist for women of color. This study analyzed maternal delivery outcomes for all women with Tricare coverage, including deliveries in the civilian sector. We analyzed data from 6.2 million births in the Centers for Disease Control (CDC) Wide-ranging Online Data for Epidemiology Research (WONDER) Linked Birth/Infant Death Records for 2017-2019. Data included all-cause morbidity (transfusions, perineal lacerations, uterine rupture, unplanned hysterectomy, and ICU admissions), severe maternal morbidity (SMM) excluding lacerations, and SMM excluding transfusion. Risk ratios were calculated by comparing overall maternal morbidity rates between Tricare, Medicaid, self-pay, and private insurance. In addition, risk ratios were calculated between insurance types stratified by race. In conclusion, there is an increased risk for women identifying as racial minorities for SMM and SMM excluding transfusion. While Tricare coverage seems to decrease the risk, the decrease is not significant and disparities in outcomes persist among women identifying as minorities. The risk of severe maternal morbidity remains elevated for women of color despite access to Tricare health insurance., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Brooke Army Medical Center Institutional Review Board (IRB) issued approval C.2019.109n /eIRB 912978. Your protocol has been APPROVED by the Human Research Protection Office. Your protocol was determined to meet the criteria for research IAW 32 CFR 219.102(l), not involving human subjects IAW 32 CFR 219.102(e)(1); therefore it will be reported as RESEARCH NOT INVOLVING HUMAN SUBJECTS. You may begin work upon receipt of this letter. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Iodice et al.)

Background: Periprosthetic femur fracture is a known complication after THA. The associated risk of cementless femoral component design for periprosthetic femur fracture in a registry population of patients older than 65 years has yet to be clearly identified., Questions/purposes: (1) Is femoral stem geometry associated with the risk of periprosthetic femur fracture after cementless THA? (2) Is the presence or absence of a collar on cementless femoral implant designs associated with the risk of periprosthetic femur fracture after THA?, Methods: We analyzed American Joint Replacement Registry data from 2012 to March 2020. Unique to this registry is the high use of cementless femoral stems in patients 65 years and older. We identified 266,040 primary cementless THAs during the study period in patients with a diagnosis of osteoarthritis and surgeries linked to supplemental Centers for Medicare and Medicaid data where available. Patient demographics, procedure dates, and reoperation for periprosthetic femur fracture with revision or open reduction and internal fixation were recorded. The main analysis was performed comparing the Kheir and Chen classification: 42% (112,231 of 266,040) were single-wedge, 22% (57,758 of 266,040) were double-wedge, and 24% (62,983 of 266,040) were gradual taper/metadiaphyseal-filling cementless femoral components, which yielded a total of 232,972 primary cementless THAs. An additional analysis compared cementless stems with collars (20% [47,376 of 232,972]) with those with collarless designs (80% [185,596 of 232,972]). A Cox proportional hazard regression analysis with the competing risk of death was used to evaluate the association of design and fracture risk while adjusting for potential confounders., Results: After controlling for the potentially confounding variables of age, sex, geographic region, osteoporosis or osteopenia diagnosis, hospital volume, and the competing risk of death, we found that compared with gradual taper/metadiaphyseal-filling stems, single-wedge designs were associated with a greater risk of periprosthetic femur fracture (HR 2.9 [95% confidence interval (CI) 2.2 to 3.9]; p < 0. 001). Compared with gradual taper/metadiaphyseal-filling stems, double-wedge designs showed an increased risk of periprosthetic femur fracture (HR 3.0 [95% CI 2.2 to 4.0]; p < 0. 001). Collarless stems showed an increased risk of periprosthetic fracture compared with collared stems (HR 7.8 [95% CI 4.1 to 15]; p < 0. 001)., Conclusion: If cementless femoral fixation is used for THA in patients 65 years or older, surgeons should consider using gradual taper/metadiaphyseal-filling and collared stem designs because they are associated with a lower risk of periprosthetic femur fracture. Future investigations should compare gradual taper/metadiaphyseal-filling and collared cementless designs with cemented fixation in this population., Level of Evidence: Level III, therapeutic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the Association of Bone and Joint Surgeons.)

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly impacted public health and the economy worldwide. Most of the currently licensed COVID-19 vaccines act by inhibiting the receptor-binding function of the SARS-CoV-2 spike protein. The constant emergence of SARS-CoV-2 variants resulting from mutations in the receptor-binding domain (RBD) leads to vaccine immune evasion and underscores the importance of broadly acting COVID-19 vaccines. Inactivated whole virus vaccines can elicit broader immune responses to multiple epitopes of several antigens and help overcome such immune evasions. We prepared a psoralen-inactivated SARS-CoV-2 vaccine (SARS-CoV-2 PsIV) and evaluated its immunogenicity and efficacy in nonhuman primates (NHPs) when administered with the Advax-CpG adjuvant. We also evaluated the SARS-CoV-2 PsIV as a booster shot in animals vaccinated with a DNA vaccine that can express the full-length spike protein. The Advax-CpG-adjuvanted SARS-CoV-2 PsIV elicited a dose-dependent neutralizing antibody response in the NHPs, as measured using a serum microneutralization assay against the SARS-CoV-2 Washington strain and the Delta variant. The animals vaccinated with the DNA vaccine followed by a boosting dose of the SARS-CoV-2 PsIV exhibited the highest neutralizing antibody responses and were able to quickly clear infection after an intranasal challenge with the SARS-CoV-2 Delta variant. Overall, the data show that the Advax-CpG-adjuvanted SARS-CoV-2 PsIV, either by itself or as a booster shot following nucleic acid (NA) vaccines, has the potential to protect against emerging variants.

Introduction: The use of antibiotic-laden bone cement (ALBC) for infection prophylaxis in the setting of primary total knee arthroplasty (TKA) remains controversial. Using data from the American Joint Replacement Registry (AJRR), (1) we examined the demographics of ALBC usage in the United States and (2) identified the effect of prophylactic commercially available ALBC on early revision and readmission for prosthetic joint infection (PJI) after primary TKA., Methods: This is a retrospective cohort study of the AJRR from 2017 to 2020. Patients older than 65 years undergoing primary cemented TKA with or without the use of commercially available antibiotic cement were eligible for inclusion (N = 251,506 patients). Data were linked to available Medicare claims to maximize revision outcomes. Demographics including age, sex, race/ethnicity, Charlson Comorbidity Index (CCI), preoperative inflammatory arthritis, region, and body mass index (BMI) class were recorded. Cox proportional hazards regression analysis was used to evaluate the association between the two outcome measures and ALBC usage., Results: Patients undergoing cemented TKA with ALBC were more likely to be Non-Hispanic Black ( P < 0.001), have a CCI of 2 or 3 ( P < 0.001), reside in the South ( P < 0.001), and had a higher mean BMI ( P < 0.001). In the regression models, ALBC usage was associated with increased risk of 90-day revision for PJI (hazards ratio 2.175 [95% confidence interval] 1.698 to 2.787) ( P < 0.001) and was not associated with 90-day all-cause readmissions. Male sex, higher CCI, and BMI >35 were all independently associated with 90-day revision for PJI., Discussion: The use of commercial ALBC in patients older than 65 years for primary TKA in the AJRR was not closely associated with underlying comorbidities suggesting that hospital-level and surgeon-level factors influence its use. In addition, ALBC use did not decrease the risk of 90-day revision for PJI and was not associated with 90-day readmission rates., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Background: Periprosthetic femur fracture (PPFx) is a devastating complication after total hip arthroplasty (THA). Despite concerns for increased PPFx, cementless fixation predominates in the United States. This study used the American Joint Replacement Registry to compare PPFx risk between cemented and cementless femoral fixation for THA., Methods: An analysis of primary THA cases in patients aged 65 years and more was performed with the American Joint Replacement Registry data linked to Centers for Medicare and Medicaid Services data from 2012 to 2020. Analyses compared cemented to cementless femoral fixation. We identified 279,052 primary THAs, 266,040 (95.3%) with cementless and 13,012 (4.7%) with cemented femoral fixation. Cox proportional hazard regression analyses evaluated the association of fixation and PPFx risk, while adjusting for sex, age, and competing risk of mortality. Cumulative incidence function survival curves evaluated time to PPFx., Results: Age ≥ 80 years (P < .0001) and women (P < .0001) were associated with PPFx. Compared to cemented stems, cementless stems had an elevated risk of PPFx (Hazards Ratio 7.70, 95% Confidence interval 3.2-18.6, P < .0001). The cumulative incidence function curves demonstrated an increased risk for PPFx across all time points for cementless stems, with equal magnitude of risk to 8 years.` CONCLUSION: Cementless femoral fixation in THA continues to predominate in the United States, with cementless femoral fixation demonstrating increased risk of PPFx in patients aged 65 years or more. Surgeons should consider greater use of cemented femoral fixation in this population to decrease the risk of PPFx., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Clear diagnostic delineation is necessary for the development of a strong evidence base in lumbar spinal surgery. Experience with existing national databases suggests that International Classification of Diseases, Tenth Edition (ICD-10) coding is insufficient to support that need. The purpose of this study was to assess agreement between surgeon-specified diagnostic indication and hospital-reported ICD-10 codes for lumbar spine surgery., Methods: Data collection for the American Spine Registry (ASR) includes an option to denote the surgeon's specific diagnostic indication for each procedure. For cases treated between January 2020 and March 2022, surgeon-delineated diagnosis was compared with the ICD-10 diagnosis generated by standard ASR electronic medical record data extraction. For decompression-only cases, the primary analysis focused on the etiology of neural compression as determined by the surgeon versus that determined on the basis of the related ICD-10 codes extracted from the ASR database. For lumbar fusion cases, the primary analysis compared structural pathology, which may have required fusion, as determined by the surgeon versus that determined on the basis of the extracted ICD-10 codes. This allowed for identification of agreement between surgeon delineation and extracted ICD-10 codes., Results: In 5926 decompression-only cases, agreement between the surgeon and ASR ICD-10 codes was 89% for spinal stenosis and 78% for lumbar disc herniation and/or radiculopathy. Both the surgeon and database indicated no structural pathology (i.e., none) suggesting the need for fusion in 88% of cases. In 5663 lumbar fusion cases, agreement was 76% for spondylolisthesis but poor for other diagnostic indications., Conclusions: Agreement between surgeon-specified diagnostic indication and hospital-reported ICD-10 codes was best for patients who underwent decompression only. In the fusion cases, agreement with ICD-10 codes was best in the spondylolisthesis group (76%). In cases other than spondylolisthesis, agreement was poor due to multiple diagnoses or lack of an ICD-10 code that reflected the pathology. This study suggested that standard ICD-10 codes may be inadequate to clearly define the indications for decompression or fusion in patients with lumbar degenerative disease.

Background: Spinal anesthesia (SP) utilization continues to expand in total knee arthroplasty (TKA). However, little is known regarding differences in complication rates between spinal and general anesthesia used for primary TKA. Therefore, the purpose of this study is to compare the length of stay (LOS), operative time, and readmission and revision rates between patients who received spinal and general anesthesia during TKA., Methods: The American Joint Replacement Registry (AJRR) was used to identify primary elective TKA patients from 2017 to 2020. Patients were divided into 2 cohorts, general (GN) and SP, based on the mode of anesthesia administered during the index surgery. In total, 270,251 TKAs were identified, of which 126,970 (47.0%) received general anesthesia and 143,281 (53.0%) received spinal anesthesia. Length of stay, operative time, 90-day readmission, and 90-day revisions were compared between the 2 groups. Multivariable logistic regression analyses were used to adjust for potential confounders., Results: After accounting for confounding factors, SP was associated with a lower risk of having a LOS greater than 3 days (odds ratio [OR] 0.470, 95% confidence interval [CI] 0.454-0.487, P < .0001), but a slightly higher likelihood of having a longer operative time (OR 1.075, 95% CI 1.056-1.094, P < .0001). SP was also linked to lower rates of 90-day readmission (OR 0.845, 95% CI 0.790-0.904, P < .0001) and lower risk of 90-day all-cause revision (OR 0.506, 95% CI 0.462-0.555, P < .0001)., Conclusion: SP was associated with a lower 90-day readmission rate and a lower risk of 90-day revision. These findings support the best practice guidelines of The Joint Commission to use spinal anesthesia when possible as part of an enhanced recovery after surgery (ERAS) pathway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction/objectives: Telehealth services expanded during the coronavirus disease 2019 (COVID-19) pandemic. Student-run free clinics (SRFC) deliver important health care services to underserved populations, who may face barriers to telehealth use. This study characterizes telehealth usage, experiences, and attitudes among individuals working in SRFCs., Methods: In November 2021, a survey adapted from the COVID-19 Healthcare Coalition Telehealth Impact Physician Survey was sent to all registrants who identified themselves as students at the 2020 Society of Student-Run Free Clinics Annual Conference., Results: Thirty-eight individuals of 576 registrants (7%) representing 21 of 88 (24%) SRFCs completed the survey. Twenty-one (58%) individuals reported using telehealth in their clinic. Those that did not cited lack of infrastructure as a barrier (eg, broadband, Internet challenges, technology investments), were more likely to serve homeless (P   =  .01), and less likely to serve non-English speaking populations (P   =  .02). There were increases in telehealth and decreases in in-person visits after March 11, 2020 though changes did not reach statistical significance. At least 15 (68%) wanted to continue chronic disease management, preventative care, and mental/behavioral health via telehealth after COVID-19. Most felt that telehealth was easy to use and improved the health, safety, and timeliness of care of patients, but not work satisfaction or access to care. Difficulty accessing physical devices, Internet, and data was the most-cited barrier to maintaining and accessing telehealth., Conclusions: Nearly all participants cited significant benefits and barriers to telehealth that impacted perceived access to care and sustainability. SRFCs' experiences may be modulated by their underserved populations and role in student education. Addressing barriers, particularly patient- and clinic-level technology challenges, could work to improve inequities in telehealth uptake.

The objective of this study was to determine the etiology of febrile illnesses among patients from October 1, 1993 through September 30, 1999, in the urban community of Iquitos in the Amazon River Basin of Peru. Epidemiological and clinical data as well as blood samples were obtained from consenting patients at hospitals, health clinics and private residences. Samples were tested for arboviruses in cell cultures and for IgM and IgG antibodies by ELISA. Blood smears were examined for malaria, and sera were tested for antibodies to Leptospira spp. by ELISA and microscopic agglutination. Among 6,607 febrile patients studied, dengue viruses caused 14.6% of the cases, and Venezuelan equine encephalitis virus caused 2.5%, Oropouche virus 1.0%, Mayaro virus 0.4%, and other arboviruses caused 0.2% of the cases. Also, 22.9% of 4,844 patients tested were positive for malaria, and of 400 samples tested, 9% had evidence of acute leptospirosis. Although the study was not designed to assess the importance of these pathogens as a cause of human morbidity in the total population, these results indicate that arboviruses, leptospirosis, and malaria were the cause of approximately 50% of the febrile cases. Although the arboviruses that were diagnosed can produce asymptomatic infections, our findings increased the overall understanding of the relative health burden of these infections, as well as baseline knowledge needed for designing and implementing further studies to better assess the health impact and threat of these pathogens in the Amazon Basin of Peru.

Background: The purpose of this study was to evaluate outcomes and complications because it relates to surgeon and hospital volume for patients undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) using the American Joint Replacement Registry from 2012 to 2017., Methods: A retrospective study was conducted on Medicare-eligible cases of primary elective THAs and TKAs reported to the American Joint Replacement Registry database and was linked with the available Centers of Medicaid and Medicare Services claims and the National Death Index data from 2012 to 2017. Surgeon and hospital volume were defined separately based on the median annual number of anatomic-specific total arthroplasty procedures performed on patients of any age per surgeon and per hospital. Values were aggregated into separate surgeon and hospital volume tertile groupings and combined to create pairwise comparison surgeon/hospital volume groupings for hip and knee., Results: Adjusted multivariable logistic regression analysis found low surgeon/low hospital volume to have the greatest association with all-cause revisions after THA (odds ratio [OR], 1.63, 95% confidence interval [CI], 1.41-1.89, P < 0.0001) and TKA (OR, 1.72, 95% CI, 1.44-2.06, P < 0.0001), early revisions because of periprosthetic joint infection after THA (OR, 2.50, 95% CI, 1.53-3.15, P < 0.0001) and TKA (OR, 2.18, 95% CI, 1.64-2.89, P < 0.0001), risk of early THA instability and dislocation (OR, 2.47, 95% CI, 1.77-3.46, P < 0.0001), and 90-day mortality after THA (OR, 1.72, 95% CI, 1.27-2.35, P = 0.0005) and TKA (OR, 1.47, 95% CI, 1.15-1.86, P = 0.002)., Conclusion: Our findings demonstrate considerably greater THA and TKA complications when performed at low-volume hospitals by low-volume surgeons. Given the data from previous literature including this study, a continued push through healthcare policies and healthcare systems is warranted to direct THA and TKA procedures to high-volume centers by high-volume surgeons because of the evident decrease in complications and considerable costs associated with all-cause revisions, periprosthetic joint infection, instability, and 90-day mortality., Level of Evidence: III., (Copyright © 2022 by the American Academy of Orthopaedic Surgeons.)

Dengue fever, caused by any of four dengue viruses (DENV1-4), is a major global burden. Currently, there is no effective vaccine that prevents infection in dengue naïve populations. We tested the ability of two novel adjuvants (Advax-PEI and Advax-2), using aluminum hydroxide (alum) as control, to enhance the immunogenicity of formalin- or psoralen-inactivated (PIV or PsIV) DENV2 vaccines in mice. Mice were vaccinated on days 0 and 30, and serum samples were collected on days 30, 60, 90, and 101. Neutralizing antibodies were determined by microneutralization (MN) assays, and the geometric mean 50% MN (MN 50 ) titers were calculated. For the PIV groups, after one dose MN 50 titers were higher in the novel adjuvant groups compared to the alum control, while MN 50 titers were comparable between the adjuvant groups after the second dose. For the PsIV groups, both novel adjuvants induced higher MN 50 titers than the alum control after the second dose. Spleen cells were collected on days 45 and 101 for enzyme-linked immunospot (ELISPOT) for IFNγ and IL4. Both PIV and PsIV groups elicited different degrees of IFNγ and IL4 responses. Overall, Advax-2 gave the best responses just ahead of Advax-PEI. Given Advax-2's extensive human experience in other vaccine applications, it will be pursued for further development.

SARS-CoV-2 has emerged as a significant cause of morbidity and mortality worldwide. Virus neutralization assays are critical for the development and evaluation of vaccines and immunotherapeutics, as well as for conducting basic research into the immune response, spread, and pathogenesis of this disease. However, neutralization assays traditionally require the use of infectious virus which must be carefully handled in a BSL-3 setting, thus complicating the assay and restricting its use to labs with access to BSL-3 facilities. Pseudovirus-based assays are an alternative to the use of infectious virus. SARS-CoV-2 pseudovirus contains only the spike structural protein, and infection results in a single round of replication, thus allowing for the assay to be run safely under BSL-2 conditions. In this chapter, we describe protocols and considerations for the production and titration of lentivirus-based SARS-CoV-2 pseudovirus, as well as for running and analysis of FACS-based pseudovirus neutralization assays., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The American Academy of Orthopaedic Surgeons American Joint Replacement Registry (AJRR) is the largest registry of total hip and knee arthroplasty (THA and TKA) procedures performed in the United States. The purpose of this study was to examine whether AJRR data are representative of the national experience with hip and knee arthroplasty as represented in the National (Nationwide) Inpatient Sample (NIS)., Methods: All patients undergoing a THA or TKA procedure between 2012 to 2018 (AJRR) and 2012 to 2016 (NIS) were identified. Cohen d effect sizes were computed to ascertain the magnitude of differences in demographics, hospital volume (in 50 patient increments), and geographic characteristics between the AJRR and NIS databases., Results: The study included (NIS: 2,316,345 versus AJRR: 557,684) primary THA and (NIS: 3,417,700 versus AJRR: 809,494) TKA procedures. The magnitude of distribution, as determined by the Cohen d effect size, showed that the proportions of AJRR and NIS patients were similar based on overall sex (THAs [d = 0.03] and TKAs [d = 0.02]) and age (THAs [d = 0.17] and TKAs [d = 0.12]). Similarly, only small differences (d = 0.34 or less) were identified between databases considering hospital volume and geography. The AJRR was underrepresented in Southern regions and hospitals with low procedure volume and overrepresented in Northern hospitals and those with larger volume. Both the NIS and the AJRR followed a similar overall trend, with most procedures performed at hospitals with <50 cases per year., Discussion: Distributions across hospital volume, age, and geography were proportionally similar between the AJRR and NIS databases, supporting the generalizability of AJRR findings to the larger US cohort., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

The development of a safe and effective vaccine to protect against COVID-19 is a global priority due to the current high SARS-CoV-2 infection rate. Currently, there are over 160 SARS-CoV-2 vaccine candidates at the clinical or pre-clinical stages of development. Of these, there are only three whole-virus vaccine candidates produced using β-propiolactone or formalin inactivation. Here, we prepared a whole-virus SARS-CoV-2 vaccine (SARS-CoV-2 PsIV) using a novel psoralen inactivation method and evaluated its immunogenicity in mice using two different adjuvants, alum and Advax-2. We compared the immunogenicity of SARS-CoV-2 PsIV against SARS-CoV-2 DNA vaccines expressing either full-length or truncated spike proteins. We also compared the psoralen-inactivated vaccine against a DNA prime, psoralen-inactivated vaccine boost regimen. After two doses, the psoralen-inactivated vaccine, when administered with alum or Advax-2 adjuvants, generated a dose-dependent neutralizing antibody responses in mice. Overall, the pattern of cytokine ELISPOT responses to antigen-stimulation observed in this study indicates that SARS-CoV-2 PsIV with the alum adjuvant promotes a Th2-type response, while SARS-CoV-2 PsIV with the Advax-2 adjuvant promotes a Th1-type response.

With increased diversity in the USA comes a growing need to educate medical students on how best to manage diverse patient populations. Medical students on the board of a student-run free clinic (SRFC) were surveyed to determine how such a leadership experience might alter students' cultural sensitivity as it relates to healthcare equity. Forty-six students (42.2% response) reported their experiences helped them better understand patient's needs (4.37, 0.64; mean, SD), cultural barriers (4.44, 0.55), and racial/ethnic disparities (4.27, 0.70). Thus, service on the board of a SRFC improves cultural sensitivity., Competing Interests: Conflict of InterestThe authors declare that there is no conflict of interest, (© International Association of Medical Science Educators 2021.)

Introduction and Background: A tetravalent DNA vaccine for Dengue virus is under development but has not yet achieved optimal immunogenicity. Salivary glands vaccination has been reported efficacious in rodents and dogs. We report on a pilot study testing the salivary gland as a platform for a Dengue DNA vaccine in a non-human primate model., Materials and Methods: Four cynomolgus macaques were used in this study. Each macaque was pre-medicated with atropine and sedated with ketamine. Stensen's duct papilla was cannulated with a P10 polyethylene tube, linked to a 500ul syringe. On the first two infusions, all macaques were infused with 300ul of TVDV mixed with 2 mg of zinc. For the 3rd infusion, to increase transfection into salivary tissue, two animals received 100uL TVDV mixed with 400uL polyethylenimine 1μg/ml (PEI) and the other two animals received 500uL TVDV with zinc. Antibody titers were assessed 4 weeks following the second and third infusion., Results and Conclusions: SGRI through Stensen's duct is a well-tolerated, simple and easy to reproduce procedure. TVDV infused into macaques salivary glands elicited a significantly weaker antibody response than with different delivery methods., Competing Interests: Competing interestsN/A, (© The Author(s) 2020.)

Dengue fever, caused by dengue viruses (DENV 1-4) is a leading cause of illness and death in the tropics and subtropics. Therefore, an effective vaccine is urgently needed. Currently, the only available licensed dengue vaccine is a chimeric live attenuated vaccine that shows varying efficacy depending on serotype, age and baseline DENV serostatus. Accordingly, a dengue vaccine that is effective in seronegative adults, children of all ages and in immunocompromised individuals is still needed. We are currently researching the use of psoralen to develop an inactivated tetravalent dengue vaccine. Unlike traditional formalin inactivation, psoralen inactivates pathogens at the nucleic acid level, potentially preserving envelope protein epitopes important for protective anti-dengue immune responses. We prepared highly purified monovalent vaccine lots of formalin- and psoralen-inactivated DENV 1-4, using Capto DeVirS and Capto Core 700 resin based column chromatography. Tetravalent psoralen-inactivated vaccines (PsIV) and formalin-inactivated vaccines (FIV) were prepared by combining the four monovalent vaccines. Mice were immunized with either a low or high dose of PsIV or FIV to evaluate the immunogenicity of monovalent as well as tetravalent formulations of each inactivation method. In general, the monovalent and tetravalent PsIVs elicited equivalent or higher titers of neutralizing antibodies to DENV than the FIV dengue vaccines and this response was dose dependent. The immunogenicity of tetravalent dengue PsIVs and FIVs were also evaluated in nonhuman primates (NHPs). Consistent with what was observed in mice, significantly higher neutralizing antibody titers for each dengue serotype were observed in the NHPs vaccinated with the tetravalent dengue PsIV compared to those vaccinated with the tetravalent dengue FIV, indicative of the importance of envelope protein epitope preservation during psoralen inactivation of DENV., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Kevin Porter holds a patent on “Psoralen-inactivated viral vaccine and method of preparation”. Patent No.: US 9005633B2]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A 28-year-old woman with a past medical history significant for cervical cancer was diagnosed with a 2.5 cm adrenal tumor but was lost to follow-up. Two years later, she presented to the emergency room with worsening right upper abdominal and flank pain. The computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen and pelvis revealed that the right adrenal mass had nearly doubled in size (4.3 cm), was heterogeneous with calcifications, central necrosis and actively uptaking the intravenous (IV) contrast with a delayed washout. The biochemical workup was negative for hyperaldosteronism, hypercortisolism, and pheochromocytoma. She reported an unintentional body weight loss of 40 pounds. Adrenocortical carcinoma or a metastatic malignancy was high on the differential diagnoses list. She underwent a successful laparoscopic adrenalectomy, and final pathology revealed a benign extra-adrenal combined ganglioneurofibroma and schwannoma. These rare benign malignancies alone or in combination may closely mimic the clinical and imaging characteristics of adrenal malignancy and pose a diagnostic and therapeutic dilemma to surgeons as well as cause a significant distress to patients and their families. Thus, it is important to thoroughly document and report these cases in order to increase awareness and improve our understanding of the biology, natural history and management of these extremely rare tumors., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Porter et al.)

A 60-year-old woman with a history of a ruptured ectopic pregnancy and subsequent salpingo-oophorectomy presented with clinical signs. Pre-operative imaging and intra-operative observations were highly suggestive of acute on chronic cholecystitis. A laparoscopic cholecystectomy was performed. In addition to confirming calculous cholecystitis, final pathology revealed endosalpingiosis on the serosal surface of the gallbladder. Endosalpingiosis is a rare, benign presence of glands lined by tubal-like epithelium, and the few case reports describe it on the surface of the female reproductive organs or seeded on the pelvic peritoneum. We hypothesize that, in this unique case, the endosalpingiosis is due to patient's ruptured ectopic pregnancy, which allowed tubal epithelial cells to spread to the gallbladder. The only documented cases of endosalpingiosis outside the pelvic and lower abdominal organs have been congenital choristomas. To our knowledge, this is the first documented case of acquired endosalpingiosis of the gallbladder., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Porter et al.)

Phase 1 clinical trials with a DNA vaccine for dengue demonstrated that the vaccine is safe and well tolerated, however it produced less than optimal humoral immune responses. To determine if the immunogenicity of the tetravalent dengue DNA vaccine could be enhanced, we explored alternate, yet to be tested, methods of vaccine administration in non-human primates. Animals were vaccinated on days 0, 28 and 91 with either a low (1 mg) or high (5 mg) dose of vaccine by the intradermal or intramuscular route, using either needle-free injection or electroporation devices. Neutralizing antibody, IFN-γ T cell and memory B cell responses were compared to a high dose group vaccinated with a needle-free intramuscular injection delivery device similar to what had been used in previous preclinical and clinical studies. All previously untested vaccination methodologies elicited improved immune responses compared to the high dose needle-free intramuscular injection delivery group. The highest neutralizing antibody responses were observed in the group that was vaccinated with the high dose formulation via intradermal electroporation. The highest IFN-γ T cell responses were also observed in the high dose intradermal electroporation group and the CD8 + T cells were the dominant contributors for the IFNγ response. Memory B cells were detected for all four serotypes. More than a year after vaccination, groups were challenged with dengue-1 virus. Both the low and high dose intradermal electroporation groups had significantly fewer days of dengue-1 virus RNAemia compared to the control group. The results from this study demonstrate that using either an electroporation device and/or the intradermal route of delivery increases the immune response generated by this vaccine in non-human primates and should be explored in humans., (Copyright © 2019. Published by Elsevier Ltd.)

A 49-year-old woman presented with clinical signs, pre-operative imaging, and intra-operative findings suggestive of acute appendicitis. A laparoscopic appendectomy was performed. Final pathology revealed a low-grade appendiceal neoplasm with serrated architecture, and secondary acute inflammation of the appendix (5 cm in length x 0.7 cm in diameter) with a congested and hemorrhagic serosal surface. The main concern in the management of patients with low-grade appendiceal mucinous neoplasm (LAMN) is that these dysplastic tumors share such similar clinical, imaging, and intraoperative features with simple acute appendicitis, which is deemed definitively cured following surgical removal of the appendix. A definitive diagnosis of LAMN is often delayed until the final pathology report; however, this finding can have implications on the further management of the patient, especially with the risk of recurrence in situations of peritoneal dissemination or positive surgical margins. Reporting LAMN cases will increase awareness of this rare disease and will contribute to improved management in the future., Competing Interests: The authors have declared that no competing interests exist.

We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin ® to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone ( N = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin ( N = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin ® ( N = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.

Introduction: Many men diagnosed with prostate cancer are concerned with how the disease and its course of treatment could affect their health-related quality of life (HRQOL). To aid in the decision-making process on a course of treatment and to better understand how these treatments can affect HRQOL, knowledge of pretreatment HRQOL is essential., Aims: To assess the racial and ethnic variations in HRQOL scores in men newly diagnosed with prostate cancer before electing a course of treatment., Methods: Male members of the Kaiser Permanente of Southern California health plan who were newly diagnosed with prostate cancer completed the five-domain specific Expanded Prostate Index Composite-26 (EPIC-26) HRQOL questionnaire from March 1, 2011 through August 31, 2013 (N = 2,579). Domain scores were compared across racial and ethnic subgroups and multiple logistic regression analyses were used to assess the association after adjusting for sociodemographic and clinical characteristics., Main Outcome Measures: The five EPIC-26 domain scores (sexual, bowel, hormonal, urinary incontinence, and urinary irritation and obstruction)., Results: Results from the fully adjusted analyses indicated that non-Hispanic black men were more likely to be above the sample median on the sexual (odds ratio [OR] = 1.43, 95% CI = 1.09-1.88), hormonal (OR = 1.35, 95% CI = 1.03-1.77), and urinary irritation and obstruction (OR = 1.34, 95% CI = 1.03-1.74) domains compared with non-Hispanic white men. The Asian or Pacific Islander men were less likely to be above the sample median on the sexual domain (OR = 0.60, 95% CI = 0.44-0.83) compared with non-Hispanic white men. No additional statistically significant differences were identified., Conclusions: Within an integrated health care organization, we found minimal racial and ethnic differences, aside from sexual function, in pretreatment HRQOL in men newly diagnosed with prostate cancer. These findings provide important insight with which to interpret HRQOL changes in men newly diagnosed with prostate cancer during and after prostate cancer treatment. Reading SR, Porter KR, Slezak JM, et al. Racial and Ethnic Variation in Health-Related Quality of Life Scores Prior to Prostate Cancer Treatment. Sex Med 2017;5:e219-e228., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The study assessed antibody-dependent NK cell degranulation, a biomarker relevant to antibody-dependent cell cytotoxicity (ADCC), to analyze dengue immune sera. We first determined binding intensity of patient sera to the surface of DENV-infected cells and examined the types of antigens expressed on infected cells. Antigens from pre-membrane (PreM) and envelope (E), but not from NS proteins were detected on the surface of infected cells. After adding NK cells to infected target cells previously treated with patient sera, rapid NK cell degranulation was observed. Non-neutralizing patient sera generated comparable NK cell degranulation as that of neutralizing sera, suggesting ADCC may be a protective mechanism apart from Ab neutralization. The level of NK cell degranulation varied dramatically among human individuals and was associated with the level of CD16 expression on NK cells, informing on the complexity of ADCC among human population., (Copyright © 2016. Published by Elsevier B.V.)

The promise of DNA vaccines is as compelling today as it was more than a decade ago. Ease of manufacture, stability at ambient temperatures without the need for a cold chain and its ability to mimic natural infections and elicit appropriate immune responses makes this vaccine platform extremely attractive. Although, human clinical trials of DNA vaccines have yielded less than optimal results, the approval and licensing of a few veterinary vaccines is testimony to the proof-of-concept and the hope that licensed DNA vaccines for human use may not be too far away. Delivery and targeting of immunologically relevant cells appears to be the major hurdle in maximizing the immunogenicity of DNA vaccines. Several different approaches that are currently pursued in achieving this objective are discussed.

The genetic basis is unknown for ∼60% of normosmic hypogonadotropic hypogonadism (nHH)/Kallmann syndrome (KS). DNAs from (17 male and 31 female) nHH/KS patients were analyzed by targeted next generation sequencing (NGS) of 261 genes involved in hypothalamic, pituitary, and/or olfactory pathways, or suggested by chromosome rearrangements. Selected variants were subjected to Sanger DNA sequencing, the gold standard. The frequency of Sanger-confirmed variants was determined using the ExAC database. Variants were classified as likely pathogenic (frameshift, nonsense, and splice site) or predicted pathogenic (nonsynonymous missense). Two novel FGFR1 mutations were identified, as were 18 new candidate genes including: AMN1, CCKBR, CRY1, CXCR4, FGF13, GAP43, GLI3, JAG1, NOS1, MASTL, NOTCH1, NRP2, PALM2, PDE3A, PLEKHA5, RD3, and TRAPPC9, and TSPAN11. Digenic and trigenic variants were found in 8/48 (16.7%) and 1/48 (2.1%) patients, respectively. NGS with confirmation by Sanger sequencing resulted in the identification of new causative FGFR1 gene mutations and suggested 18 new candidate genes in nHH/KS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine the racial and ethnic variation in time to prostate biopsy after an elevated screening level of serum prostate-specific antigen (PSA)., Methods: Male members of the Kaiser Permanente of Southern California health plan, 45 years of age or older, with no history of prostate cancer or a prostate biopsy, and at least 1 elevated screening level of serum PSA between January 1, 1998 and December 31, 2007 were retrospectively identified (n = 59,506). All participants were passively followed via electronic health records until their time of prostate biopsy, death, membership disenrollment, or study conclusion (December 31, 2014), whichever was the initial event. Proportional hazard regression analyses were used to estimate the association between time from an elevated screening level of serum PSA to prostate biopsy, adjusting for age, benign prostatic hyperplasia, prostatitis, type 2 diabetes mellitus, hypertension, and Charlson Comorbidity Index score., Results: Median time until biopsy was 0.6 years (214 days), with approximately 41% of participants receiving a prostate biopsy within the study period. Results from the fully adjusted analysis indicated that the non-Hispanic Asian or Pacific Islanders (hazard ratio: 1.10, 95% confidence interval: [1.04, 1.15]) and the non-Hispanic blacks (hazard ratio: 1.04, 95% confidence interval: [1.00, 1.08]) had a slightly shorter time to prostate biopsy after an elevated screening level of serum PSA compared to the non-Hispanic whites., Conclusion: These data suggest that, within an integrated healthcare organization, minimal differences exist between racial and ethnic subgroups in their time to prostate biopsy after an elevated screening level of serum PSA., (Copyright © 2016. Published by Elsevier Inc.)

Background: Dengue has emerged as one of the most important infectious diseases in the last five decades. Evidence indicates the expansion of dengue virus endemic areas and consequently the exponential increase of dengue virus infections across the subtropics. The clinical manifestations of dengue virus infection include sudden fever, rash, headache, myalgia and in more serious cases, spontaneous bleeding. These manifestations occur in children as well as in adults. Defining the epidemiology of dengue in a given area is critical to understanding the disease and devising effective public health strategies., Methodology/principal Findings: Here, we report the results from a prospective cohort study of 4380 adults in West Java, Indonesia, from 2000-2004 and 2006-2009. A total of 2167 febrile episodes were documented and dengue virus infections were confirmed by RT-PCR or serology in 268 cases (12.4%). The proportion ranged from 7.6 to 41.8% each year. The overall incidence rate of symptomatic dengue virus infections was 17.3 cases/1,000 person years and between September 2006 and April 2008 asymptomatic infections were 2.6 times more frequent than symptomatic infections. According to the 1997 WHO classification guidelines, there were 210 dengue fever cases, 53 dengue hemorrhagic fever cases (including one dengue shock syndrome case) and five unclassified cases. Evidence for sequential dengue virus infections was seen in six subjects. All four dengue virus serotypes circulated most years. Inapparent dengue virus infections were predominantly associated with DENV-4 infections., Conclusions/significance: Dengue virus was responsible for a significant percentage of febrile illnesses in an adult population in West Java, Indonesia, and this percentage varied from year to year. The observed incidence rate during the study period was 43 times higher than the reported national or provincial rates during the same time period. A wide range of clinical severity was observed with most infections resulting in asymptomatic disease. The circulation of all four serotypes of dengue virus was observed in most years of the study.

Since the early 1990s, DNA immunization has been used as a platform for developing a tetravalent dengue vaccine in response to the high priority need for protecting military personnel deployed to dengue endemic regions of the world. Several approaches have been explored ranging from naked DNA immunization to the use of live virus vectors to deliver the targeted genes for expression. Pre-clinical animal studies were largely successful in generating anti-dengue cellular and humoral immune responses that were protective either completely or partially against challenge with live dengue virus. However, Phase 1 clinical evaluation of a prototype monovalent dengue 1 DNA vaccine expressing prM and E genes revealed anti-dengue T cell IFNγ responses, but poor neutralizing antibody responses. These less than optimal results are thought to be due to poor uptake and expression of the DNA vaccine plasmids. Because DNA immunization as a vaccine platform has the advantages of ease of manufacture, flexible genetic manipulation and enhanced stability, efforts continue to improve the immunogenicity of these vaccines using a variety of methods., (Published by Elsevier Ltd.)

Purpose: The date of cancer diagnosis is a critical data element for clinical care and research. Because this date can be abstracted from various data sources, its comparability from source to source is unclear. This study compared the date of diagnosis from multiple sources within the same population of prostate cancer patients., Methods: We linked cancer registry, pathology report, and electronic health data sources from the Kaiser Permanente Southern California health data systems for a cohort of 22,666 members diagnosed with prostate cancer between 2000 and 2010. The magnitude and direction of the differences in date of diagnosis were assessed for each date pairwise comparison. We reviewed 454 medical records to determine reasons for date discrepancies., Results: Among the date pairwise comparisons, differences in date of diagnosis spanned from 9.6 years earlier to 10 years later than each other. However, the overall median difference ranged from 1 to 16 days, thus suggesting that the vast majority of the date differences were small. Chart review results identified major categories of date discrepancies., Conclusions: These data demonstrate variability in date of diagnosis across these data sources. This variability may have implications for epidemiologic estimates or patient identification in research studies using different data sources., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Results from several studies suggest that there is value in evaluating the association between nonclinical characteristics of patients and quality of life (QoL), but few studies have focused on brain cancer. The primary goal of this feasibility study was to explore the relationship between clinical factors and nonclinical factors and QoL in brain cancer patients., Methods: Participants in this cross-sectional study were drawn from two hospital sites. Eligible patients were 18-75 years old with a pathologically confirmed diagnosis of a brain cancer histology and stable disease after treatment. Data were obtained from medical chart review and a self-administered survey consisting of main study variables and two QoL standardized measures. Independent sample t test was used to determine differences between patient factors and QoL measures., Results: The sample population was comprised of 26 patients with a median age at survey of 57.5 years (range 33-72). Quality of life was adversely associated with younger age, having underage children and living alone. Patients' meaning of QoL differed by gender, however most patients viewed it as affecting multiple aspects of their lives., Conclusions: Nonclinical characteristics were significantly associated with QoL more often than clinical characteristics. Identifying these factors may help improve the quality of care for these patients. This effort demonstrates the relevancy and feasibility of conducting a larger scale study to confirm or refute these findings.

Dengue is the most important arbovirus worldwide and is the virus that causes dengue fever and the more severe dengue hemorrhagic fever. There are four serotypes of dengue with each possessing the ability to cause disease. Developing a preventive vaccine is the most efficient and effective way to prevent these diseases, and because immunity to one serotype does not protect against the other serotypes, a vaccine must provide tetravalent protection. We used DNA immunization as a platform to develop a tetravalent vaccine. In this chapter, we describe the laboratory, regulatory, and clinical methodology for evaluating a candidate tetravalent vaccine in a Phase 1 clinical trial.

Chikungunya virus (CHIKV) is known to cause sporadic or explosive outbreaks. However, little is known about the endemic transmission of CHIKV. To ascertain the endemic occurrence of CHIKV transmission, we tested blood samples from patients with a non-dengue febrile illness who participated in a prospective cohort study of factory workers in Bandung, Indonesia. From August 2000 to June 2004, and September 2006 to April 2008, 1901 febrile episodes occurred and 231 (12.2%) dengue cases were identified. The remaining febrile cases were evaluated for possible CHIKV infection by measuring anti-CHIKV IgM and IgG antibodies in acute and convalescent samples. Acute samples of serologically positive cases were subsequently tested for the presence of CHIKV RNA by RT-PCR and/or virus isolation. A total of 135 (7.1%) CHIKV infections were identified, providing an incidence rate of 10.1/1,000 person years. CHIKV infections were identified all year round and tended to increase during the rainy season (January to March). Severe illness was not found and severe arthralgia was not a prominently reported symptom. Serial post-illness samples from nine cases were tested to obtain a kinetic picture of IgM and IgG anti-CHIKV antibodies. Anti-CHIKV IgM antibodies were persistently detected in high titers for approximately one year. Three patients demonstrated evidence of possible sequential CHIKV infections. The high incidence rate and continuous chikungunya cases in this adult cohort suggests that CHIKV is endemically transmitted in Bandung. Further characterization of the circulating strains and surveillance in larger areas are needed to better understand CHIKV epidemiology in Indonesia.

We investigated whether statin use is associated with reduced risk of recurrence in prostate cancer patients who undergo radiotherapy. A retrospective cohort of 774 patients from a California health plan was followed for 5 years. Statin use prior to, during and after radiotherapy was not associated with prostate cancer recurrence [hazard ratio=0.99 (0.70-1.39), 0.87 (0.62-1.22) and 0.78 (0.55-1.09), respectively] in multivariable Cox models. No clear dose-response relationship was observed for average daily statin dose or duration of statin use. Our findings do not support a preventive benefit of statins in prostate cancer recurrence after radiotherapy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Statins have shown broad spectrum anti-cancer properties in laboratory studies. In epidemiological studies, use of statins has been associated with reduced risk of advanced prostate cancer. However, the effects of statins on prostate cancer disease progression following curative treatment have not been extensively studied, and previous studies reported conflicting results. This study found no clear association between overall statin use and risk of disease progression, as well as lack of a monotone dose-response relationship between the use of statins, whether it was use before or after prostatectomy, and prostate cancer disease progression., Objective: To investigate whether use of HMG-CoA reductase inhibitors ('statins'), which have shown broad spectrum anti-cancer properties in laboratory studies, is associated with a reduced risk of recurrence in patients with prostate cancer who undergo radical prostatectomy., Patients and Methods: All men with incident prostate cancer diagnosed between 2004 and 2005 who subsequently underwent radical prostatectomy by the end of 2005 in the Kaiser Permanente Southern California (KPSC) health plan were identified using KPSC's cancer registry. Subjects were followed for up to 5 years after prostatectomy for (i) biochemical recurrence, defined as a single PSA measurement >0.2 ng/mL, and (ii) clinical disease progression, defined as diagnosis of metastatic disease or prostate-cancer-related death. Information on statin use, demographics, comorbidities, patho-clinical factors and outcomes were ascertained from KPSC's electronic medical records. The effects of statin use prior to and after prostatectomy were both examined using bivariate and multivariate Cox models, adjusting for known prognostic factors. For postoperative statin exposure, a time-dependent Cox model was used., Results: A total of 1200 men were included; 37% had preoperative and 56% had postoperative statin use. Neither preoperative nor postoperative statin use was associated with biochemical recurrence (hazard ratio [HR] = 1.00 [0.72-1.39] and 1.05 [0.76-1.46], respectively) or clinical disease progression (HR = 0.63 [0.31-1.27] and 1.20 [0.63-2.30], respectively). No clear dose-response relationship was found for duration of use., Conclusions: Statin use may not prevent prostate cancer progression following radical prostatectomy. These findings do not provide support for the pursuit of a prospective clinical trial of statin use as a secondary prevention among surgically treated patients with prostate cancer., (© 2013 BJU International.)

Objective: To investigate the racial/ethnic differences in the time to treatment among patients with prostate cancer., Materials and Methods: All 3448 men diagnosed with localized prostate cancer at Kaiser Permanente Southern California from 2006 to 2007 were identified. The patients were passively followed up through their electronic health records until definitive treatment, defined as the first treatment given with curative intent within 1 year of diagnosis. Cox proportional hazard models, with PROC SURVEYPHREG procedures, were used to account for the variability in time to the different treatments within multiple medical centers., Results: The overall median time to treatment was 102 days, with modest differences for whites (100 days), blacks (104 days), and Hispanics (99 days). In the adjusted model, black men had a significantly longer time to surgery (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.91) compared with white men. Hispanic men (adjusted hazard ratio 1.44, 95% confidence interval 1.07-1.74) experienced significantly shorter times to radiotherapy compared with white men. No difference was found in the time to radiotherapy or brachytherapy for black men relative to white men., Conclusion: These data suggest that minimal racial/ethnic differences exist in the time to treatment after the diagnosis of prostate cancer in this equal-access setting. This is encouraging, but does not mean that all men were satisfied with their treatment choice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A prototype dengue-1 DNA vaccine was shown to be safe and immunogenic in a previous Phase 1 clinical trial. Anti-dengue-1 neutralizing antibody responses were detectable only in the group of volunteers receiving the high dose of nonadjuvanted vaccine and the antibody titers were low. Vaxfectin(®), a lipid-based adjuvant, enhances the immunogenicity of DNA vaccines. We conducted a nonhuman primate study to evaluate the effect of Vaxfectin(®) on the immunogenicity of a tetravalent dengue DNA vaccine. Animals were immunized on days 0, 28 and 84, with each immunization consisting of 3mg of Vaxfectin(®)-adjuvanted tetravalent dengue DNA vaccine. The use of Vaxfectin(®) resulted in a significant increase in anti-dengue neutralizing antibody responses against dengue-1, -3 and -4. There was little to no effect on T cell responses as measured by interferon gamma ELISPOT assay. Animals immunized with the Vaxfectin(®)-formulated tetravalent DNA vaccine showed significant protection against live dengue-2 virus challenge compared to control animals (0.75 mean days of viremia vs 3.3 days). Animals vaccinated with nonadjuvanted DNA had a mean 2.0 days of viremia. These results support further evaluation of the Vaxfectin(®)-adjuvanted tetravalent dengue DNA vaccine in a Phase 1 clinical trial., (Published by Elsevier Ltd.)

Vaccination with plasmid DNA against infectious pathogens including dengue is an active area of investigation. By design, DNA vaccines are able to elicit both antibody responses and cellular immune responses capable of mediating long-term protection. Great technical improvements have been made in dengue DNA vaccine constructs and trials are underway to study these in the clinic. The scope of this review is to highlight the rich history of this vaccine platform and the work in dengue DNA vaccines accomplished by scientists at the Naval Medical Research Center. This work resulted in the only dengue DNA vaccine tested in a clinical trial to date. Additional advancements paving the road ahead in dengue DNA vaccine development are also discussed., (Published by Elsevier Ltd.)

Psoralens are photoreactive compounds that cross-link pyrimidines after exposure to UVA radiation. In this experiment, we tested the protective efficacy of a psoralen-inactivated dengue vaccine candidate in non-human primates. Two groups of 7 Aotus nancymaae monkeys received either 10ng per dose of inactivated DENV1 plus alum adjuvant or alum alone (controls). Doses were injected intradermally on days 0, 14, and 28. Monkeys then received a challenge inoculation of 1.1 × 10(4)PFUs of WestPac 74 DENV-1 on day 132. At 62 days, only 1/7 vaccinated monkeys had detectable IgM, but IgG and neutralizing antibody remained detectable in 7/7. No IgM, IgG, or neutralizing antibody was detectable in control monkeys. DENV-1 viremia was detected after challenge in 3/7 vaccinated monkeys and 5/6 control monkeys (with one removed due to pregnancy) (p=0.27), but days of viremia were reduced from 3.67 days/animal among controls to 0.71 days/animal among vaccinated monkeys (p=0.051). Psoralen-inactivated DENV1 is immunogenic in Aotus nancymaae with a trend towards a reduction in days of viremia following experimental challenge., (Published by Elsevier Ltd.)

Candidate dengue DNA vaccine constructs for each dengue serotype were developed by incorporating pre-membrane and envelope genes into a plasmid vector. A Phase 1 clinical trial was performed using the dengue virus serotype-1 (DENV-1) vaccine construct (D1ME(100)). The study was an open-label, dose-escalation, safety and immunogenicity trial involving 22 healthy flavivirus-naïve adults assigned to one of two groups. Each group received three intramuscular injections (0, 1, and 5 months) of either a high dose (5.0mg, n=12) or a low dose (1.0mg, n=10) DNA vaccine using the needle-free Biojector(®) 2000. The most commonly reported solicited signs and symptoms were local mild pain or tenderness (10/22, 45%), local mild swelling (6/22, 27%), muscle pain (6/22, 27%) and fatigue (6/22, 27%). Five subjects (41.6%) in the high dose group and none in the low dose group developed detectable anti-dengue neutralizing antibodies. T-cell IFN gamma responses were detected in 50% (4/8) and 83.3% (10/12) of subjects in the low and high dose groups, respectively. The safety profile of the DENV-1 DNA vaccine is acceptable at both doses administered in the study. These results demonstrate a favorable reactogenicity and safety profile of the first in human evaluation of a DENV-1 DNA vaccine., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Survival statistics commonly reflect survival from the time of diagnosis but do not take into account survival already achieved after a diagnosis. The objective of this study was to provide conditional survival estimates for brain tumor patients as a more accurate measure of survival for those who have already survived for a specified amount of time after diagnosis., Methods: Data on primary malignant and nonmalignant brain tumor cases diagnosed from 1985-2005 from selected SEER state cancer registries were obtained. Relative survival up to 15 years postdiagnosis and varying relative conditional survival rates were computed using the life-table method., Results: The overall 1-year relative survival estimate derived from time of diagnosis was 67.8% compared to the 6-month relative conditional survival rate of 85.7% for 6-month survivors (the probability of surviving to 1 year given survival to 6 months). The 10-year overall relative survival rate was 49.5% from time of diagnosis compared to the 8-year relative conditional survival rate of 79.2% for 2-year survivors. Conditional survival estimates and standard survival estimates varied by histology, behavior, and age at diagnosis. The 5-year relative survival estimate derived from time of diagnosis for glioblastoma was 3.6% compared to the 3-year relative conditional survival rate of 36.4% for 2-year survivors. For most nonmalignant tumors, the difference between relative survival and the corresponding conditional survival estimates were minimal. Older age groups had greater numeric gains in survival but lower conditional survival estimates than other age groups. Similar findings were seen for other conditional survival intervals., Conclusions: Conditional survival is a useful disease surveillance measure for clinicians and brain tumor survivors to provide them with better 'real-time' estimates and hope., (Copyright © 2011 S. Karger AG, Basel.)

OBJECT Patients having a primary tumor of the spinal cord, spinal meninges or cauda equina, are relatively rare. Neurosurgeons encounter and treat such patients, and need to be aware of their clinical presentation, tumor types, treatment options, and potential complications. The purpose of this paper is to report results from a series of 430 patients with primary intraspinal tumors, taken from a larger cohort of 9661 patients with primary tumors of the CNS. METHODS Extensive information on individuals diagnosed (in the year 2000) as having a primary CNS neoplasm was prospectively collected in a Patient Care Evaluation Study conducted by the Commission on Cancer of the American College of Surgeons. Data from US hospital cancer registries were submitted directly to the National Cancer Database. Intraspinal tumor cases were identified based on ICD-O-2 topography codes C70.1, C72.0, and C72.1. Analyses were performed using SPSS. RESULTS Patients with primary intraspinal tumors represented 4.5% of the CNS tumor group, and had a mean age of 49.3 years. Pain was the most common presenting symptom, while the most common tumor types were meningioma (24.4%), ependymoma (23.7%), and schwannoma (21.2%). Resection, surgical biopsy, or both were performed in 89.3% of cases. Complications were low, but included neurological worsening (2.2%) and infection (1.6%). Radiation therapy and chemotherapy were administered to 20.3% and 5.6% of patients, respectively. CONCLUSIONS Data from this study are suitable for benchmarking, describing prevailing patterns of care, and generating additional hypotheses for future studies.

Prevalence is the best indicator of cancer survivorship in the population, but few studies have focused on brain tumor prevalence because of previous data limitations. Hence, the full impact of primary brain tumors on the healthcare system in the United States is not completely described. The present study provides an estimate of the prevalence of disease in the United States, updating an earlier prevalence study. Incidence data for 2004 and survival data for 1985-2005 were obtained by the Central Brain Tumor Registry of the United States from selected regions, modeled under 2 different survival assumptions, to estimate prevalence rates for the year 2004 and projected estimates for 2010. The overall incidence rate for primary brain tumors was 18.1 per 100 000 person-years with 2-, 5-, 10-, and 20-year observed survival rates of 62%, 54%, 45%, and 30%, respectively. On the basis of the sum of nonmalignant and averaged malignant estimates, the overall prevalence rate of individuals with a brain tumor was estimated to be 209.0 per 100 000 in 2004 and 221.8 per 100 000 in 2010. The female prevalence rate (264.8 per 100 000) was higher than that in males (158.7 per 100 000). The averaged prevalence rate for malignant tumors (42.5 per 100 000) was lower than the prevalence for nonmalignant tumors (166.5 per 100 000). This study provides estimates of the 2004 (n = 612 770) and 2010 (n = 688 096) expected number of individuals living with primary brain tumor diagnoses in the United States, providing more current and robust estimates for aiding healthcare planning and patient advocacy for an aging US population.