A Gammaherpesviral Internal Repeat Contributes to Latency Amplification

BACKGROUND: Gammaherpesviruses cause important infections of humans, in particular in immunocompromised patients. The genomes of gammaherpesviruses contain variable numbers of internal repeats whose precise role for in vivo pathogenesis is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We used infection of laboratory mice with murine gammaherpesvirus 68 (MHV-68) to explore the biological role of the 40 bp internal repeat of MHV-68. We constructed several mutant viruses partially or completely lacking this repeat. Both in vitro and in vivo, the loss of the repeat did not substantially affect lytic replication of the mutant viruses. However, the extent of splenomegaly, which is associated with the establishment of latency, and the number of ex vivo reactivating and genome positive splenocytes were reduced. Since the 40 bp repeat is part of the hypothetical open reading frame (ORF) M6, it might function as part of M6 or as an independent structure. To differentiate between these two possibilities, we constructed an N-terminal M6STOP mutant, leaving the repeat structure intact but rendering ORF M6 unfunctional. Disruption of ORF M6 did neither affect lytic nor latent infection. In contrast to the situation in lytically infected NIH3T3 cells, the expression of the latency-associated genes K3 and ORF72 was reduced in the latently infected murine B cell line Ag8 in the absence of the 40 bp repeat. CONCLUSIONS/SIGNIFICANCE: These data suggest that the 40 bp repeat contributes to latency amplification and might be involved in the regulation of viral gene expression

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Analysis of Postoperative Pain at the Anterior Iliac Crest Harvest Site: A Prospective Study of the Intraoperative Local Administration of Ropivacaine

Study DesignThis was a prospective randomized comparative study.PurposeThe aim of this study was to objectify donor site-related pain following anterior iliac crest graft harvesting, in patients who have undergone multilevel anterior cervical discectomy and fusion with plating (ACDFP); and to assess the effect of an intraoperative local single injection of ropivacaine on postoperative pain.Overview of LiteratureMultilevel ACDFP can be associated with a high non-union rate. Autogenous iliac bone has been used to increase union rates, although a high incidence of donor site-related pain has been reported.MethodsForty consecutive patients who required 3-level or 4-level ACDFP were prospectively assessed for donor site-related pain. Pain levels were assessed daily for five days postoperative using the visual analog scale (VAS). Patients were randomly assigned to group A or B. In group A patients, 7-10 mL of ropivacaine (0.2%) was injected into the iliac crest after iliac crest graft harvesting. Morphine usage via patient controlled analgesia was calculated. At six months postoperative, patient complaints at the harvest site were documented.ResultsPatients were randomly assigned to group A or B. In group A, ropivacaine was locally administered at the site of the iliac crest graft harvest after fascia closure. In group B, no additional treatments were administered. The average patient age in group A was 56±7.6 years, whereas the average age of patients in group B was 52.6±10.4 years. Group A had an average of 0.6±0.7 previous surgeries per patient, whereas group B had an average of 0.8±1.0 previous surgeries per patient. The average number of levels fused in group A was 3.6±0.7, whereas the average number of levels fused in group B was 3.7±0.9 (all p>0.05). In group A, the mean ropivacaine volume administered was 8.4±1.5 mL. No patient complaints regarding chronic pain, were reported six months postoperatively. No complications were encountered from the harvest site, and all patients underwent successful 3-level and 4-level ACDFP. Statistical analysis showed significant differences for VAS on postoperative day 1 (p=0.004) and day 2 (p=0.005).ConclusionsVAS assessment showed overall moderate perioperative morbidity in terms of donor site-related pain, which was reduced by administering ropivacaine

Feasibility of the Far Lateral Suboccipital Approach to the Retroodontoid Region. How Much Bone Removal Is Truly Needed?

Objective The posterolateral extradural suboccipital approach can be used to reach the anterior epidural space and the retro-odontoid regions. The extent of necessary bone removal of the atlas vertebra (C1) has not yet been defined. We studied the changes in the size of the horizontal and vertical surgical windows using stepwise bone removal of C1. A representative case is shown. Methods The anatomical study was performed bilaterally on five Thiel-fixed human cadavers (mean age, 83.7 years). The surgical window (horizontal × vertical) required to access the retro-odontoid region via a posterolateral approach was measured for an intact C1 posterior arch, after a semicircular inferior partial resection of the C1 arch, after resection of the unilateral hemiarch of C1, and finally after drilling approximately 3 mm from the medial aspect of the lateral mass of C1. Results The intact C1 resulted in a very narrow surgical window of 6.3 mm × 9.7 mm (horizontal × vertical). The vertical window increased to a 13 mm after the semicircular inferior partial resection of the C1 arch and to 17.3 mm in the case of removal of the ipsilateral C1 posterior arch. The bone removal from the medial aspect of the C1 lateral mass resulted in a widening of the horizontal surgical window to 10.3 mm. The final size of the surgical window was 10.3 mm × 17.3 mm. The patient with severe kyphoscoliosis of the craniocervical spine was successfully operated on using odontoid and C1–2 facet osteotomies. Conclusion If only the anterior epidural space or the base of the odontoid needs to be reached, the semicircular inferior partial resection of the C1 arch allows for an adequate surgical window. The tip of the odontoid could only be reached if the ipsilateral posterior arch is resected

Surgical nuances and construct patterns influence construct stiffness in C1-2 stabilizations: a biomechanical study of C1-2 gapping and advanced C1-2 fixation

Purpose!#!Stabilization of C1-2 using a Harms-Goel construct with 3.5 mm titanium (Ti) rods has been established as a standard of reference (SOR). A reduction in craniocervical deformities can indicate increased construct stiffness at C1-2. A reduction in C1-2 can result in C1-2 joint gapping. Therefore, the authors sought to study the biomechanical consequences of C1-2 gapping on construct stiffness using different instrumentations, including a novel 6-screw/3-rod (6S3R) construct, to compare the results to the SOR. We hypothesized that different instrument pattern will reveal significant differences in reduction in ROM among constructs tested.!##!Methods!#!The range of motion (ROM) of instrumented C1-2 polyamide models was analyzed in a six-degree-of-freedom spine tester. The models were loaded with pure moments (2.0 Nm) in axial rotation (AR), flexion extension (FE), and lateral bending (LB). Comparisons of C1-2 construct stiffness among the constructs included variations in rod diameter (3.5 mm vs. 4.0 mm), rod material (Ti. vs. CoCr) and a cross-link (CLX). Construct stiffness was tested with C1-2 facets in contact (Contact Group) and in a 2 mm distracted position (Gapping Group). The ROM (°) was recorded and reported as a percentage of ROM (%ROM) normalized to the SOR. A difference > 30% between the SOR and the %ROM among the constructs was defined as significant.!##!Results!#!Among all constructs, an increase in construct stiffness up to 50% was achieved with the addition of CLX, particularly with a 6S3R construct. These differences showed the greatest effect for the CLX in AR testing and for the 6S3R construct in FE and AR testing. Among all constructs, C1-2 gapping resulted in a significant loss of construct stiffness. A protective effect was shown for the CLX, particularly using a 6S3R construct in AR and FE testing. The selection of rod diameter (3.5 mm vs. 4.0 mm) and rod material (Ti vs. CoCr) did show a constant trend but did not yield significance.!##!Conclusion!#!This study is the first to show the loss of construct stiffness at C1-2 with gapping and increased restoration of stability using CLX and 6S3R constructs. In the correction of a craniocervical deformity, nuances in the surgical technique and advanced instrumentation may positively impact construct stability

Resolution of the lumbosacral fractional curve and evaluation of the risk for adding on in 101 patients with posterior correction of Lenke 3, 4, and 6 curves

OBJECTIVE In double and triple major adolescent idiopathic scoliosis curves it is still controversial whether the lowest instrumented vertebra (LIV) should be L3 or L4. Too short a fusion can impede postoperative distal curve compensation and promote adding on (AON). Longer fusions lower the chance of compensation by alignment changes of the lumbosacral curve (LSC). This study sought to improve prediction accuracy for AON and surgical outcomes in Lenke type 3, 4, and 6 curves.METHODS This was a retrospective multicenter analysis of patients with adolescent idiopathic scoliosis who had Lenke 3, 4, and 6 curves and >= 1 year of follow-up after posterior correction. Resolution of the LSC was studied by changes of LIV tilt, L3 tilt, and L4 tilt, with the variables resembling surrogate measures for the LSC. AON was defined as a disc angle below LIV > 5 degrees at follow-up. A matched-pairs analysis was done of differences between LIV at L3 and at L4. A multivariate prediction analysis evaluated the AON risk in patients with LIV at L3. Clinical outcomes were assessed by the Scoliosis Research Society 22-item questionnaire (SRS-22).RESULTS The sample comprised 101 patients (average age 16 years). The LIV was L3 in 54%, and it was L4 in 39%. At follow-up, 87% of patients showed shoulder balance, 86% had trunk balance, and 64% had a lumbar curve (LC) 5 20 degrees. With an LC 5 20 degrees (p = 0.01), SRS-22 scores were better and AON was less common (26% vs 59%, p = 0.001). Distal extension of the fusion (e.g., LIV at L4) did not have a significant influence on achieving an LSC < 20 degrees; however, higher screw density allowed better LC correction and resulted in better spontaneous LSC correction. AON occurred in 34% of patients, or 40% if the LIV was L3. Patients with AON had a larger residual LSC, worse LC correction, and worse thoracic curve (TC) correction. A total of 44 patients could be included in the matched-pairs analysis. LC correction and TC correction were comparable, but AON was 50% for LIV at L3 and 18% for LIV at L4. Patients without AON had a significantly better LC correction and TC correction (p < 0.01). For patients with LIV at L3, a significant prediction model for AON was established including variables addressed by surgeons: postoperative LC and TC (negative predictive value 78%, positive predictive value 79%, sensitivity 79%, specificity 81%).CONCLUSIONS An analysis of 101 patients with Lenke 3, 4, and 6 curves showed that TC and LC correction had significant influence on LSC resolution and the risk for AON. Improving LC correction and achieving an LC < 20 degrees offers the potential to lower the risk for AON, particularly in patients with LIV at L3

Diagnostic accuracy of CT scan-based criteria compared with surgical exploration for the analysis of cervical fusion and nonunion

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