Radiation exposure in multiple hereditary exostoses: A retrospective review.

Background: Exposure to ionizing radiation in patients with Multiple Hereditary Exostoses (MHE) is inevitable and necessary for the diagnosis and treatment of MHE. Radiation exposure has many potentially dangerous consequences, including the increased risk of developing cancer. This is especially concerning in the pediatric patient population since children are more likely to develop adverse effects from radiation than adults. This study aimed to quantify radiation exposure over a five-year period among patients diagnosed with MHE since such information is not currently available in the literature. Methods: Diagnostic radiographs, computed tomography (CT) scans, nuclear medicine studies, and intraoperative fluoroscopy exposures were analyzed for radiation exposure in 37 patients diagnosed with MHE between 2015 and 2020. Results: Thirty-seven patients with MHE underwent 1200 imaging studies, 976 of which were related to MHE and 224 unrelated to MHE. The mean estimated MHE cumulative radiation dose per patient was 5.23 mSv. Radiographs related to MHE contributed the most radiation. Patients from the ages of 10- to 24-years-old received the most imaging studies and exposure to ionizing radiation, especially compared to those under age 10 (P = 0.016). The 37 patients also received a total of 53 surgical-excision procedures, with a mean of 1.4 procedures per person. Conclusions: MHE patients are exposed to increased levels of ionizing radiation secondary to serial diagnostic imaging, with those ages 10-24 years old being exposed to significantly higher doses of radiation. Because pediatric patients are more sensitive to radiation exposure and are at an overall higher risk, the use of radiographs should always be justified in those patients.

N-3 Long Chain Fatty Acids Supplementation, Fatty Acids Desaturase Activity, and Colorectal Cancer Risk: A Randomized Controlled Trial.

INTRODUCTION: n-3 long-chain polyunsaturated fatty acids (LCPUFA) have anti-inflammatory effects and may reduce colorectal cancer risk. The purpose of this study was to evaluate the effects of n-3 LCPUFA supplementation on markers of rectal cell proliferation and apoptosis and examine how genetic variation in desaturase enzymes might modify this effect. METHODS: We conducted a randomized, double-blind, control six-month trial of 2.5 grams of n-3 LCPUFA per day compared to olive oil. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1). Our primary outcome was change in markers of rectal epithelial proliferation and apoptosis. RESULTS: A total of 141 subjects were randomized. We found no difference in apoptosis markers between participants randomized to n-3 LCPUFA compared to olive oil (P = 0.41). N-3 LCPUFA supplementation increased cell proliferation in the lower colonic crypt compared to olive oil (P = 0.03) however baseline indexes of proliferation were different between the groups at randomization. We found no evidence that genotype modified the effect. CONCLUSIONS: Our study did not show evidence of a proliferative or pro-apoptotic effect on n-3 LCPUFA supplementation on rectal mucosa regardless of the FADS genotype.ClinicalTrials.gov Identifier: NCT01661764Supplemental data for this article is available online at https://dx.doi.org/10.1080/01635581.2021.1955286.

The Current State of the Residency Match.

This article explores the current state of the residency match in 2020 with a focus on orthopedic surgery, analyzing the utility of current applicant screening methods in producing future generations of competent surgeons. Discussed are anticipated changes to the residency application process considering the COVID-19 pandemic and Step 1 becoming pass/fail in January 2022. Also explored are potential changes to improve the process for applicants and residency programs, such as identifying and using predictive factors of resident success in the applicant screening process, finding better ways to match applicants with programs, and increasing female and underrepresented minorities within orthopedics.

Is NBATS-2 up to the Task? Actual vs. Predicted Patient Volume Shifts With the Addition of Another Trauma Center.

INTRODUCTION: Version 2 of the Needs-Based Assessment of Trauma Systems (NBATS) tool quantifies the impact of an additional trauma center on a region. This study applies NBATS-2 to a system where an additional trauma center was added to compare the tool's predictions to actual patient volumes. METHODS: Injury data were collected from the trauma registry of the initial (legacy) center and analyzed geographically using ArcGIS. From 2012 to 2014 ("pre-"period), one Level 1 trauma center existed. From 2016 to 2018 ("post-"period), an additional Level 2 center existed. Emergency medical service (EMS) destination guidelines did not change and favored the legacy center for severely injured patients (Injury Severity Score (ISS) >15). NBATS-2 predicted volume was compared to the actual volume received at the legacy center in the post-period. RESULTS: 4068 patients were identified across 14 counties. In the pre-period, 72% of the population and 90% of injuries were within a 45-minute drive of the legacy trauma center. In the post-period, 75% of the total population and 90% of injuries were within 45 minutes of either trauma center. The post-predicted volume of severely injured patients at the legacy center was 434, but the actual number was 809. For minor injuries (ISS £15), NBATS-2 predicted 581 vs. 1677 actual. CONCLUSION: NBATS-2 failed to predict the post-period volume changes. Without a change in EMS destination guidelines, this finding was not surprising for severely injured patients. However, the 288% increase in volume of minor injuries was unexpected. NBATS-2 must be refined to assess the impact of local factors on patient volume.

Location, location, location: Utilizing Needs-Based Assessment of Trauma Systems-2 in trauma system planning.

BACKGROUND: In 2015, the American College of Surgeons Committee on Trauma introduced the Needs-Based Assessment of Trauma Systems (NBATS) tool to quantify the optimal number of trauma centers for a region. While useful, more focus was required on injury population, distribution, and transportation systems. Therefore, NBATS-2 was developed utilizing advanced geographical modeling. The purpose of this study was to evaluate NBATS-2 in a large regional trauma system. METHODS: Data from all injured patients from 2016 to 2017 with an Injury Severity Score greater than 15 was collected from the trauma registry of the existing (legacy) center. Injury location and demographics were analyzed by zip code. A regional map was built using US census data to include hospital and population demographic data by zip code. Spatial modeling was conducted using ArcGIS to estimate an area within a 45-minute drive to a trauma center. RESULTS: A total of 1,795 severely injured patients were identified across 54 counties in the tri-state region. Forty-eight percent of the population and 58% of the injuries were within a 45-minute drive of the legacy trauma center. With the addition of another urban center, injured and total population coverage increased by only 1% while decreasing the volume to the existing center by 40%. However, the addition of two rural trauma centers increased coverage significantly to 62% of the population and 71% of the injured (p < 0.001). The volume of the legacy center was decreased by 25%, but the self-pay rate increased by 16%. CONCLUSION: The geospatial modeling of NBATS-2 adds a new dimension to trauma system planning. This study demonstrates how geospatial modeling applied in a practical tool can be incorporated into trauma system planning at the local level and used to assess changes in population and injury coverage within a region, as well as potential volume and financial implications to a current system. LEVEL OF EVIDENCE: Care management/economic, level V.

Postgraduate publishing output in pediatric neurosurgery: correlation with fellowship site and individual scholars.

OBJECTIVE: The objective of this study was to analyze the publication output of postgraduate pediatric neurosurgery fellows for a 10-year period as well as identify 25 individual highly productive pediatric neurosurgeons. The correlation between academic productivity and the site of fellowship training was studied. METHODS: Programs certified by the Accreditation Council for Pediatric Neurosurgery Fellowships that had 5 or more graduating fellows from 2006 to 2015 were included for analysis. Fellows were queried using Scopus for publications during those 10 years with citation data through 2017. Pearson correlation coefficients were calculated, comparing program rankings of faculty against fellows using the revised Hirsch index (r-index; primary) and Hirsch index (h-index; secondary). A list of 25 highly accomplished individual academicians and their fellowship training locations was compiled. RESULTS: Sixteen programs qualified with 152 fellows from 2006 to 2015; 136 of these surgeons published a total of 2009 articles with 23,735 citations. Most publications were pediatric-specific (66.7%) clinical articles (93.1%), with middle authorship (55%). Co-investigators were more likely from residency than fellowship. There was a clustering of the top 7 programs each having total publications of around 120 or greater, publications per fellow greater than 12, more than 1200 citations, and adjusted ir10 (revised 10-year institutional h-index) and ih10 (10-year institutional h-index) values of approximately 2 or higher. Correlating faculty and fellowship program rankings yielded correlation coefficients ranging from 0.53 to 0.80. Fifteen individuals (60%) in the top 25 (by r5 index) list completed their fellowship at 1 of these 7 institutions. CONCLUSIONS: Approximately 90% of fellowship-trained pediatric neurosurgeons have 1 or more publications, but the spectrum of output is broad. There is a strong correlation between where surgeons complete their fellowships and postgraduate publications.

The impact of Recovery Colleges on mental health staff, services and society.

AIMS: Recovery Colleges are opening internationally. The evaluation focus has been on outcomes for Recovery College students who use mental health services. However, benefits may also arise for: staff who attend or co-deliver courses; the mental health and social care service hosting the Recovery College; and wider society. A theory-based change model characterising how Recovery Colleges impact at these higher levels is needed for formal evaluation of their impact, and to inform future Recovery College development. The aim of this study was to develop a stratified theory identifying candidate mechanisms of action and outcomes (impact) for Recovery Colleges at staff, services and societal levels. METHODS: Inductive thematic analysis of 44 publications identified in a systematised review was supplemented by collaborative analysis involving a lived experience advisory panel to develop a preliminary theoretical framework. This was refined through semi-structured interviews with 33 Recovery College stakeholders (service user students, peer/non-peer trainers, managers, community partners, clinicians) in three sites in England. RESULTS: Candidate mechanisms of action and outcomes were identified at staff, services and societal levels. At the staff level, experiencing new relationships may change attitudes and associated professional practice. Identified outcomes for staff included: experiencing and valuing co-production; changed perceptions of service users; and increased passion and job motivation. At the services level, Recovery Colleges often develop somewhat separately from their host system, reducing the reach of the college into the host organisation but allowing development of an alternative culture giving experiential learning opportunities to staff around co-production and the role of a peer workforce. At the societal level, partnering with community-based agencies gave other members of the public opportunities for learning alongside people with mental health problems and enabled community agencies to work with people they might not have otherwise. Recovery Colleges also gave opportunities to beneficially impact on community attitudes. CONCLUSIONS: This study is the first to characterise the mechanisms of action and impact of Recovery Colleges on mental health staff, mental health and social care services, and wider society. The findings suggest that a certain distance is needed in the relationship between the Recovery College and its host organisation if a genuine cultural alternative is to be created. Different strategies are needed depending on what level of impact is intended, and this study can inform decision-making about mechanisms to prioritise. Future research into Recovery Colleges should include contextual evaluation of these higher level impacts, and investigate effectiveness and harms.

Steady-state amprenavir, tenofovir, and emtricitabine pharmacokinetics before and after reducing ritonavir boosting of a fosamprenavir/tenofovir/emtricitabine regimen from 200 mg to 100 mg once daily (TELEX II).

PURPOSE: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. METHODS: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. RESULTS: Baseline median minimum plasma concentration (Cmin) and area under the plasma concentration-time curve over 24 hours post dose (AUC24h) were as follows: APV: 1,708 ng/mL, 84,260 h * ng/mL; tenofovir: 53 ng/mL, 2,420 h * ng/mL; FTC: 58 ng/mL, 9,190 h * ng/mL; RTV: 80 ng/mL, 10,230 h * ng/mL. Four weeks after reducing RTV, changes in Cmin and AUC24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV -64%, -79%. Component plasma concentration ranges were consistent with historical values. Median APV Cmin was 14.7-fold above the protein-binding-adjusted 50% inhibitory concentration of wild-type HIV. Four weeks after RTV reduction, HIV-1 RNA levels remained <50 copies/mL in all patients, median CD4+ count increased from 465 to 495 cells/mm3, and favorable lipid changes and no adverse events were observed. CONCLUSION: Reducing RTV boosting from 200 to 100 mg QD of FPV/TDF/FTC QD conferred no detrimental effect on APV, tenofovir, FTC, or RTV pharmacokinetics and maintained virologic suppression.

Characterization of virulence factors of mouse-adapted Helicobacter pylori strain SS1 and effects on gastric hydrophobicity.

Gastric infection with Helicobacter pylori results in chronic active gastritis and in some individuals is associated with complications such as peptic ulceration and gastric cancers. A balance between bacterial factors and host responses may determine disease outcome. The mouse-adapted H. pylori strain SS1 has been utilized as a model to study disease pathogenesis. Although chronic gastritis is observed in this murine model of H. pylori infection, other complications of disease seen in the human host (such as peptic ulceration) are not identified. The objectives of this study were to characterize virulence factors of the mouse-adapted H. pylori strain SS1 and determine host responses to infection. Vacuolating cytotoxin activity of H. pylori strain SS1 was determined after incubation of HEp-2 cells with culture supernatant for 24 hr. Polymerase chain reaction was performed to detect the presence of the cagA and cagE genes. Chemokine responses from human gastric epithelial cells infected with H. pylori SS1 were assessed by measurement of the concentration of interleukin-8 in cell-free supernatants. C57BL/6 and gld mice were infected with strain SS1 or sham-infected. Eight weeks following infection, gastric tissues were obtained for histological analysis and surface hydrophobicity was measured by axisymmetric drop-shape analysis. H. pylori strain SS1 was cytotoxin negative, cagA positive, and cagE positive, but induced only a modest interleukin-8 response (684 +/- 140 pg/ml) from AGS gastric epithelial cells in comparison to a clinical isolate (4170 +/- 410 pg/ml, P < 0.0005). Increased inflammation was observed in the stomachs of H. pylori strain SS1-infected animals compared to uninfected controls. Gastritis was not associated with any disease complications. Despite mucosal inflammation, infected mice did not demonstrate alterations in gastric surface hydrophobicity (42.2 degrees +/- 2.2 degrees and 41.4 degrees +/- 3.2 degrees for C57BL/6 and gld, respectively) compared to uninfected mice (43.2 degrees +/- 2.3 degrees and 39.5 degrees +/- 1.6 degrees, respectively). In conclusion, murine infection with H. pylori SS1, which contains putative bacterial virulence factors, results in gastric inflammation. However, the mucosal changes are not associated with alterations in surface hydrophobicity. Therefore, the mouse model of infection with H. pylori, strain SS1 may not serve as an entirely appropriate model to study host factors associated with disease complications.

Multifunctionalized alpha,beta-cyclopentenones from C-2 and C-4-ulopyranosyl compounds: a stereospecific rearrangement initiated by base.

Base treatment of O-benzyl protected C-2- or C-4-ulopyranosyl compounds (4 alpha, 4 beta, and 11) by either 10% Et(3)N or 1% K(2)CO(3) in MeOH initiated a beta elimination to afford alpha,beta-unsaturated C-ulopyranosyl compounds (5 alpha, 5 beta, and 12), which further rearranged in a stereocontrolled manner to multifuctionalized alpha,beta-cyclopentenones (6 and 14) in 70-80% yield. Both C-alpha- and C-beta-2-ulosides (5 alpha and 5 beta) produced the same cyclopentenone 6, indicating that a 1,2-enolate is formed prior to the cleavage of the C-5--O bond. Because 6 is racemic, it was probably formed by the intramolecular cycloaldolization of two equally populated enantiomeric intermediates. When treated with 90% Et(3)N in MeOH, 5 alpha yielded almost exclusively 15 (isomer of 6), which was formed by a migration of the double bond in 5 alpha during the previously described rearrangement. Thus either 6 or 15 was the major product, depending on the base used.

Levofloxacin failure in a patient with pneumococcal pneumonia.

OBJECTIVE: To report a case of levofloxacin failure in a patient with a penicillin-sensitive Streptococcus pneumoniae pneumonia. CASE SUMMARY: A previously healthy, immunocompetent, 53-year-old white man presented with penicillin-sensitive S. pneumoniae pneumonia. The patient was empirically placed on levofloxacin monotherapy, which was continued due to a local penicillin shortage. When the patient failed to improve, further susceptibility testing was ordered. The organism was found to have a penicillin minimum inhibitory concentration (MIC) of 0.023 microgram/mL and a levofloxacin MIC of 6 micrograms/mL. Effective antimicrobial therapy was delayed, as clinicians did not anticipate fluoroquinolone resistance. DISCUSSION: Newer fluoroquinolones such as levofloxacin have good activity against most S. pneumoniae isolates and are used for the treatment of pneumonia. Although resistance to these agents is rare, it has been reported. Current guidelines from the National Committee for Clinical Laboratory Standards do not recommend initial fluoroquinolone susceptibility testing. CONCLUSIONS: As fluoroquinolone resistance may not be identified by susceptibility patterns to other antibiotics, early fluoroquinolone susceptibility testing and increased awareness of resistance may aid clinicians in their treatment of pneumococcal disease.

Construction of multivalent sialyl Le(x) from the type Ia group B Streptococcus capsular polysaccharide.

The type Ia group B Streptococcus (GBSIa) capsular polysaccharide was specifically degraded by partial Smith oxidation of 2,3-diol of the Glc in the backbone to fragments representing asialo core repeating units. Sialylation of these oligomers furnished GBSIa multiple repeating units. One, two and three repeating units of GBSIa were obtained pure, and the higher oligomers were obtained as mixtures. After enzymatic fucosylation oligosaccharides carrying bivalent, trivalent and other multivalent sialyl Le(x) epitopes presented as appendages on an oligolactoside scaffold were obtained.

Immunostimulant oxidized beta-glucan conjugates.

beta-Glucans are polysaccharides that act as nonspecific immune system stimulants. However, many beta-Glucans are sparingly soluble in water. This work describes an oxidative procedure, which solubilizes the beta-Glucan from Saccharomyces cerevisiae and maintains its immunostimulatory properties. Furthermore, the carboxylates at the site of oxidation allow for the conjugation of small molecule immunostimulants. Both the parent oxidized beta-glucan and its conjugates with O-beta-alanyl-5-[6-(N,N'-dimethylamino)purin-9-yl]pentanol stimulate cytotoxic T-lymphocytes (CTLs), B cells and macrophages. In addition, they both stimulate natural killer (NK) cells, a property which the small molecule purine does not possess.

The conformational epitope of type III group B Streptococcus capsular polysaccharide.

In order to further characterize the conformational epitope of GBSPIII, we synthesized various oligosaccharides with the GBSPIII-related structures by a tailor-assembly synthetic scheme and a more traditional block-wise chemo-enzymatic approach. The oligosaccharides were used to probe the conformational epitope of GBSPIII using number of complementary techniques. The protective epitope of GPSPIII was further defined as length-dependent and conformational. The results of the studies confirmed that two repeating units (2RU) is the minimum binding unit and the epitope optimization mainly takes place between chain length 2RU to 7RU. Epitope optimization and multivalency were observed between 7RU and 20RU. The data support our hypothesis that the conformational epitope is an extended helical segment of the GBSPIII. GBSPIII exists mainly in the random coil form, which structurally mimics short oligosaccharide self-antigens, but it can infrequently and spontaneously form extended helices. Although not prevalent in GBSPIII the immune system preferentially selects these helical epitopes because they are unique to the polysaccharide.

NMR and molecular modeling of complex carbohydrates and carbohydrate-protein interactions. Applications to anti-bacteria vaccines.

In order to characterize the conformational epitope of the group B meningococcal polysaccharide and of the type III group B Streptococcus capsular polysaccharide NMR measurements were done on a wide variety of native and modified polysaccharides and oligosaccharides. Since these saccharides are highly mobile and exist as random coils in solution, the analysis of the NMR data and molecular modeling was done to take into account this inherent flexibility. The conformational model of extended high-order helices being selected upon binding to a protein, although still hypothetical at this stage, has proven useful in explaining the serology for the conformational epitopes for polysaccharides of group B Neisseria meningitidis, group B Streptococcus type III and Streptococcus pneumoniae type 14.

Purification of capsular polysaccharide.

Meningococcus is an aerobic, fastidious, Gram-negative diplococcus that is found only in humans. Its cell wall has a cytoplasmic membrane, a peptidoglycan layer, and an outer membrane. Meningococci isolated from the bloodstream or the spinal fluid are almost always encapsulated. The capsules are polysaccharides, which consist of repeating sugar units (1,2). The capsular polysaccharide can be isolated, purified, and chemically and physically defined. Based on the chemical and immunological specificity of its capsular polysaccharides, Neisseria meningitidis has been classified serologically into groups A, B, C, 29E, H, I, K, L, W135, X, Y and Z (2). Of these, groups A, B, and C are responsible for approx 90% of meningococcal meningitis, and group B meningococcus is responsible for the majority of meningococcal disease in industrialized countries (1,2). The structures of the repeating units of the meningococcal polysaccharides have been elucidated and are shown in Table 1. Table 1 Structures of the Capsular Polysaccharides of N. meningitidis Group Structure of repeating unit Reference A →6)α-D-ManNAc(1-PO4→ (8) 3 ↑ OAc B →8)α-D-NeuNAc(2→ (5) C →9)α-D-NeuNAc(2→ (5) 7/8 ↑ OAc H →4)α-D-Gal (l→2) glycerol 3-PO(4)→ (6) L →3)α-D-GlcNAc (l→3) ß-D-GlcNAc (l→3) α-D-GlcNAc-1-PO(4)→ (7) X →4)α-D-GlcNAc-1 -PO(4)→ (4) Y →6)α-D-Glc (l→4) α-D-NeuNAc (2→ (OAc) (9) W135 →6)α-D-Gal (l→4) α-D-NeuNAc (2→ (9) Z →3)α-D-GalNAc (1→1) glycerol 3-PO(4)→ (10) 29E →7)ß-D-KDO (l→3) α-D-GalNAc (l→ (11).

Protein-polysaccharide conjugation.

The use of bacterial capsular polysaccharides as immunoprophylactic agents in human diseases caused by encapsulated bacteria is now firmly established (1). However, despite their many advantages, they do have serious limitations. First, they induce an inadequate immune response in infants (2), the section of the population most vulnerable to bacterial meningitis, and second, some polysaccharides are only weakly immunogenic in adults. To overcome these deficiencies, a new generation of semisynthetic vaccines have been developed based on the conjugation of polysaccharide to protein carriers.

N-propionylation.

Serogroup B Neisseria meningitidis remains a major world health problem and currently there is no fully efficacious vaccine available. The poor immunogenicity of the group B meningococcal polysaccharide both in adults and infants prevents the formulation of a comprehensive polysaccharide-based vaccine (1). Although, as discussed in Chapter 4 , conjugation technology can overcome the limitation of the poor immunogenicity of most capsular polysaccharides, the serogroup B meningococcal polysaccharide when conjugated to a protein carrier still failed to give a significant immune response (2,3). This phenomenon is probably attributed to the molecular mimicry between the polysaccharide and human-tissue antigens. As shown in Fig. 1, the serogroup B polysaccharide is a homopolymer of α(2-8)-linked sialic-acid residues (4) and similar structures have also been identified in the humantissue antigens, from short trimeric fragments found in mammalian gangliosides (5) to long decameric fragments observed in the glycoproteins of neural-cell adhesion molecules (N-CAMs) (6). Fig. 1. Chemical structure of GBMP.