Magnetic resonance imaging in the evaluation of cervical foraminal stenosis: comparison of 3D T2 SPACE with sagittal oblique 2D T2 TSE.

OBJECTIVE: The oblique orientation of the cervical neural foramina challenges the implementation of a short MRI protocol with concurrent excellent visualization of the spine. While sagittal oblique T2-weighted sequences permit good evaluation of the cervical neuroforamina, all segments may not be equally well depicted on a single sequence and conspicuity of foraminal stenosis may be limited. 3D T2-weighted sequences can be reformatted in arbitrary planes, including the sagittal oblique. We set out to compare 3D T2w SPACE sequences with sagittal oblique reformations and sagittal oblique 2D T2w TSE sequences for the evaluation of cervical foraminal visibility and stenosis. MATERIALS AND METHODS: Sixty consecutive patients who underwent MRI of the cervical spine with sagittal oblique 2D T2w TSE and 3D T2w SPACE sequences were included. Image homogeneity of the sequences was evaluated. Imaging sets were assessed for structure visibility and foraminal stenosis by two independent readers. Results of the sequences were compared by Wilcoxon matched-pairs tests. Interreader agreement was evaluated by weighted κ. RESULTS: Visibility of most structures was rated good to excellent on both sequences (mean visibility scores ≥ 4.5 of 5), though neuroforaminal contents were better seen on sagittal oblique T2w TSE (mean scores 4.1-4.6 vs. 3.1-4.1 on 3D T2w SPACE, p < 0.01). Stenosis grades were comparable between sequences (mean 1.1-2.6 of 4), with slightly higher values for 3D T2w SPACE at some levels (difference ≤ 0.3 points). CONCLUSION: 3D T2w SPACE is comparable with sagittal oblique 2D T2w TSE in the evaluation of cervical neural foramina.

Three-dimensional analysis for quantification of knee joint space width with weight-bearing CT: comparison with non-weight-bearing CT and weight-bearing radiography.

OBJECTIVE: To compare computer-based 3D-analysis for quantification of the femorotibial joint space width (JSW) using weight-bearing cone beam CT (WB-CT), non-weight-bearing multi-detector CT (NWB-CT), and weight-bearing conventional radiographs (WB-XR). DESIGN: Twenty-six participants prospectively underwent NWB-CT, WB-CT, and WB-XR of the knee. For WB-CT and NWB-CT, the average and minimal JSW was quantified by 3D-analysis of the minimal distance of any point of the subchondral tibial bone surface and the femur. Associations with mechanical leg axes and osteoarthritis were evaluated. Minimal JSW of WB-CT was further compared to WB-XR. Two-tailed p-values of <0.05 were considered significant. RESULTS: Significant differences existed of the average medial and lateral JSW between WB-CT and NWB-CT (medial: 4.7 vs 5.1 mm [P = 0.028], lateral: 6.3 vs 6.8 mm [P = 0.008]). The minimal JSW on WB-XR (medial:3.1 mm, lateral:5.8 mm) were significantly wider compared to WB-CT and NWB-CT (both medial:1.8 mm, lateral:2.9 mm, all p < 0.001), but not significantly different between WB-CT and NWB-CT (all p ≥ 0.869). Significant differences between WB-CT and NWB-CT existed in participants with varus knee alignment for the average and the minimal medial JSW (p = 0.004 and p = 0.011) and for participants with valgus alignment for the average lateral JSW (p = 0.013). On WB-CT, 25% of the femorotibial compartments showed bone-on-bone apposition, which was significantly higher when compared to NWB-CT (10%,P = 0.008) and WB-XR (8%,P = 0.012). CONCLUSION: Combining WB-CT with 3D-based assessment allows detailed quantification of the femorotibial joint space and the effect of knee alignment on JSW. WB-CT demonstrates significantly more bone-on-bone appositions, which are underestimated or even undetectable on NWB-CT and WB-XR.

The Restless Spinal Cord in Degenerative Cervical Myelopathy.

BACKGROUND AND PURPOSE: The spinal cord is subject to a periodic, cardiac-related movement, which is increased at the level of a cervical stenosis. Increased oscillations may exert mechanical stress on spinal cord tissue causing intramedullary damage. Motion analysis thus holds promise as a biomarker related to disease progression in degenerative cervical myelopathy. Our aim was characterization of the cervical spinal cord motion in patients with degenerative cervical myelopathy. MATERIALS AND METHODS: Phase-contrast MR imaging data were analyzed in 55 patients (37 men; mean age, 56.2 [SD,12.0] years; 36 multisegmental stenoses) and 18 controls (9 men, P = .368; mean age, 62.2 [SD, 6.5] years; P = .024). Parameters of interest included the displacement and motion pattern. Motion data were pooled on the segmental level for comparison between groups. RESULTS: In patients, mean craniocaudal oscillations were increased manifold at any level of a cervical stenosis (eg, C5 displacement: controls [n = 18], 0.54 [SD, 0.16] mm; patients [n = 29], monosegmental stenosis [n = 10], 1.86 [SD, 0.92] mm; P < .001) and even in segments remote from the level of the stenosis (eg, C2 displacement: controls [n = 18], 0.36 [SD, 0.09] mm; patients [n = 52]; stenosis: C3, n = 21; C4, n = 11; C5, n = 18; C6, n = 2; 0.85 [SD, 0.46] mm; P < .001). Motion at C2 differed with the distance to the next stenotic segment and the number of stenotic segments. The motion pattern in most patients showed continuous spinal cord motion throughout the cardiac cycle. CONCLUSIONS: Patients with degenerative cervical myelopathy show altered spinal cord motion with increased and ongoing oscillations at and also beyond the focal level of stenosis. Phase-contrast MR imaging has promise as a biomarker to reveal mechanical stress to the cord and may be applicable to predict disease progression and the impact of surgical interventions.

Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine.

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

Segmental differences of cervical spinal cord motion: advancing from confounders to a diagnostic tool.

Increased cranio-caudal spinal cord motion is associated with clinical impairment in degenerative cervical myelopathy. However, whether spinal cord motion holds potential as a neuroimaging biomarker requires further validation. Different confounders (i.e. subject characteristics, methodological problems such as phase drift, etc.) on spinal cord motion readouts have to be considered. Twenty-two healthy subjects underwent phase contrast MRI, a subset of subjects (N = 9) had repeated scans. Parameters of interest included amplitude of velocity signal, maximum cranial respectively maximum caudal velocity, displacement (=area under curve of the velocity signal). The cervical spinal cord showed pulse synchronic oscillatory motions with significant differences in all readouts across cervical segments, with a maximum at C5. The Inter-rater reliability was excellent for all readouts. The test-retest reliability was excellent for all parameters at C2 to C6, but not for maximum cranial velocity at C6 and all readouts at C7. Spinal cord motion was correlated with spinal canal size, heart rate and body size. This is the first study to propose a standardized MRI measurement of spinal cord motion for further clinical implementation based on satisfactory phase drift correction and excellent reliability. Understanding the influence of confounders (e.g. structural conditions of the spine) is essential for introducing cord motion into the diagnostic work up.

Synovial C-reactive protein features high negative predictive value but is not useful as a single diagnostic parameter in suspected periprosthetic joint infection (PJI).

OBJECTIVES: Synovial fluid C-reactive protein (syCRP) has been recently described as a new biomarker in preoperative diagnostics to identify periprosthetic joint infections (PJI). The aim of this study was to evaluate syCRP in a large cohort of patients with suspected PJI and to calculate the optimal cut-off to diagnose PJI. METHODS: Between September 2015 and June 2017, we prospectively included patients with suspected PJI, in which syCRP was additionally measured along with routine preoperative diagnostic serum and synovial biomarkers. We analysed the sensitivity and specificity of syCRP using receiver operating characteristic curves. RESULTS: We included 192 cases (hip n = 80, knee n = 91, shoulder n = 21) with a final diagnosis of PJI in 26 cases (14.0%). Combined for all joints, the syCRP values were significantly higher in the PJI group than in the no PJI group (median: 13.8 vs. 0 mg/l; p < 0.001). The optimal cut-off (Youden Index: 0.71) for the PJI diagnosis combined for all joints was at a syCRP value of 2.9 mg/l with a sensitivity of 88%, a specificity of 82%, and a negative predictive value of 98%. CONCLUSIONS: SyCRP features high negative predictive value but is not useful as a single diagnostic parameter in suspected periprosthetic joint infection (PJI).

Fast-track versus long-term hospitalizations for patients with non-disabling acute ischaemic stroke.

BACKGROUND AND PURPOSE: The aim was to assess the feasibility and safety of fast-track hospitalizations in a selected cohort of patients with stroke. METHODS: Patients hospitalized at the Stroke Center of the University Hospital Basel, Switzerland, with an acute ischaemic stroke confirmed on magnetic resonance diffusion-weighted imaging were included. Neurological deficits of the included patients were non-disabling, i.e. not interfering with activities of daily living and compatible with a direct discharge home. Patients with premorbid disability were excluded. All patients were admitted to the Stroke Center for ≥24 h. Two study groups were compared - fast-track hospitalizations (≤72 h) and long-term hospitalizations (>72 h). The primary end-point was a composite of any unplanned rehospitalization for any reason within 3 months since hospital discharge and a modified Rankin Scale 3-6 at 3 months. Adjustment for confounders was done using the inverse probability of treatment weights (IPTW). RESULTS: Amongst the 521 patients who met the inclusion criteria, fast-track hospitalizations were performed in 79 patients (15%). In the fast-track group, seven patients (8.9%) met the primary end-point, compared to 37 (8.4%) in the long-term group [odds ratio (OR) 1.06, 95% confidence interval (CI) 0.42-2.34, P = 0.88]. After weighting for IPTW, the odds of the primary end-point remained similar between the two arms (ORIPTW 1.27, 95% CI 0.51-3.16, P = 0.61). The costs of fast-track hospitalizations were lower, on average, by $4994. CONCLUSIONS: Fast-track hospitalizations including a full workup proved to be feasible, showed no increased risk and were less expensive than long-term hospitalizations.

Inflammatory disorders mimicking periprosthetic joint infections may result in false-positive α-defensin.

OBJECTIVES: The antimicrobial peptide α-defensin has recently been introduced as a potential 'single' biomarker with a high sensitivity and specificity for the preoperative diagnosis of periprosthetic joint infections (PJIs). However, most studies assessed the benefits of the test with exclusion of patients with rheumatic diseases. We aimed to evaluate the α-defensin test in a cohort study without exclusion of people with inflammatory diseases. METHODS: Between June 2016 and June 2017, we prospectively included cases with a suspected PJI and an available lateral flow test α-defensin (Synovasure®) in synovial fluid. We compared the test result to the diagnostic criteria for PJIs published by an International Consensus Group in 2013. RESULTS: We included 109 cases (49 hips, 60 knees) in which preoperative α-defensin tests had been performed. Among these, 20 PJIs (16 hips, four knees) were diagnosed. Preoperative α-defensin tests were positive in 25 cases (22.9%) with a test sensitivity and specificity of 90% and 92.1% (95% CI 68.3%-98.8% and 84.5%-96.8%, respectively), and a high negative predictive value of 97.6% (95% CI 91.7%-99.4%). We interpreted seven α-defensin tests as false positive, mainly in cases with inflammatory rheumatic diseases, including crystal deposition diseases. CONCLUSIONS: A negative synovial α-defensin test can reliably rule out a PJI. However, the test can be false positive in conjunction with an underlying non-infectious inflammatory disease. We therefore propose to use the α-defensin test only in combination with Musculoskeletal Infection Society criteria and assessment for crystals in synovial aspirates.

Serum neurofilament light chain in patients with acute cerebrovascular events.

BACKGROUND AND PURPOSE: Serum neurofilaments are markers of axonal injury. We addressed their diagnostic and prognostic role in acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: Nested within a prospective cohort study, we compared levels of serum neurofilament light chain (sNfL) drawn within 24 h from symptom onset in patients with AIS or TIA. Patients without magnetic resonance imaging on admission were excluded. We assessed whether sNfL was associated with: (i) clinical severity on admission, (ii) diagnosis of AIS vs. TIA, (iii) infarct size on admission magnetic resonance diffusion-weighted imaging (MR-DWI) and (iv) functional outcome at 3 months. RESULTS: We analyzed 504 patients with AIS and 111 patients with TIA. On admission, higher National Institutes of Health Stroke Scale (NIHSS) scores were associated with higher sNfL: NIHSS score < 7, 13.1 pg/mL [interquartile range (IQR), 5.3-27.8]; NIHSS score 7-15, 16.7 pg/mL (IQR, 7.4-34.9); and NIHSS score > 15, 21.0 pg/mL (IQR, 9.3-40.4) (P = 0.01). Compared with AIS, patients with TIA had lower sNfL levels [9.0 pg/mL (95% confidence interval, 4.0-19.0) vs. 16.0 pg/mL (95% confidence interval, 7.3-34.4), P < 0.001], also after adjusting for age and NIHSS score (P = 0.006). Among patients with AIS, infarct size on admission MR-DWI was not associated with sNfL, either in univariate analysis (P = 0.15) or after adjusting for age and NIHSS score on admission (P = 0.56). Functional outcome 3 months after stroke was not associated with sNfL after adjusting for established predictors. CONCLUSIONS: In conclusion, among patients admitted within 24 h of AIS or TIA onset, admission sNfL levels were associated with clinical severity on admission and TIA diagnosis, but not with infarct size on MR-DWI acquired on admission or functional outcome at 3 months.

Mid- to long-term results of total ankle replacement in patients with haemophilic arthropathy: A 10-year follow-up.

INTRODUCTION: Haemophilic ankle arthropathy is caused by recurrent spontaneous joint haemorrhaging and leads to pain, deformity and loss of function. In the presence of advanced articular deterioration, therapeutic options are confined to either arthroplasty or arthrodesis, the latter still being referred to as the procedure of choice. However, total ankle replacement (TAR) has recently gained acceptance as an alternative. AIM: To investigate the mid- to long-term results of TAR in haemophilic ankle arthropathy. MATERIALS AND METHODS: Seventeen TARs in 14 male patients (mean age: 43 years [range, 27.4-57.6]), implanted between 1998 and 2012, were retrospectively analysed. Implant survival was estimated using Kaplan-Meier analysis. Haemophilic/viral status, complications and revision surgeries were recorded. Follow-up assessment of 12 TARs was performed 9.6 years (range, 3.3-17.8) postoperatively, including clinical examination, pain and satisfaction scales, the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score, and the SF-36. Radiographic evaluation of pre- and follow-up radiographs was conducted. RESULTS: Estimated implant survival was 94% at 5, 85% at 10 and 70% at 15 years, respectively. Three cases required revision surgery. At follow-up, 9.6 years (range, 3.3-17.8) postoperatively, the level of satisfaction was 76% (range, 50-100) and of pain 2/10 (range, 0-6) on the VAS. Range of motion had increased significantly (P = .037). The SF-36 summary scores were comparable to those of a matched standard population. The AOFAS hindfoot score averaged 81 points (range, 73-90). All radiographs revealed component loosening or periprosthetic radiolucency. CONCLUSION: Total ankle replacement in the presence of advanced haemophilic arthropathy is a viable treatment option with favourable mid-/long-term results, maintaining mobility of the ankle joint.

Distinguishing in-hospital and out-of-hospital status epilepticus: clinical implications from a 10-year cohort study.

BACKGROUND AND PURPOSE: The aim was to determine differences of clinical, treatment and outcome characteristics between patients with in-hospital and out-of-hospital status epilepticus (SE). METHODS: From 2005 to 2014, clinical data were assessed in adults with SE treated in an academic medical care centre. Clinical characteristics, treatment and outcomes were compared between patients with in-hospital and out-of-hospital SE. RESULTS: Amongst 352 patients, 213 were admitted with SE and 139 developed in-hospital SE. Patients with in-hospital SE had more acute/fatal aetiologies (60% vs. 35%, P < 0.001), fewer previous seizures (33% vs. 50%, P = 0.002), a higher median Charlson Comorbidity Index (3 vs. 2, P < 0.001), longer median SE duration (1 vs. 0.5 days, P = 0.001), more refractory SE (52% vs. 39%, P = 0.022), less return to functional baseline (38% vs. 54%, P = 0.006) and increased mortality (29% vs. 19%, P = 0.001). Whilst in multivariable analyses an increasing Status Epilepticus Severity Score (STESS) was an independent predictor for death in both groups, increased Charlson Comorbidity Index and treatment refractory SE were associated with death only in patients with in-hospital SE. Continuous anaesthesia for refractory SE was associated with increased mortality only in patients with out-of-hospital SE. The area under the receiver operating curve was 0.717 for prediction of death by STESS in patients with in-hospital SE and 0.811 in patients with out-of-hospital SE. CONCLUSIONS: Patients with in-hospital SE had more fatal aetiologies and comorbidities, refractory SE, less return to functional baseline, and increased mortality compared to patients with out-of-hospital SE. Whilst the STESS was a robust predictor for death in both groups, the association between continuous anaesthesia and death was limited to out-of-hospital SE.

Early predictors of refractory status epilepticus: an international two-center study.

BACKGROUND AND PURPOSE: Status epilepticus (SE) refractory to first- and second-line antiepileptic drugs carries high mortality. Little is known on early prediction of refractory SE (RSE)­an essential tool for planning appropriate therapy. Our aim was to identify and validate independent early RSE predictors in adults. METHODS: Clinical and laboratory data on consecutive intensive care unit patients with SE from two academic care centers (a derivation data set from a Swiss center and a validation data set from a US center) were assessed. Multivariable analysis was performed with the derivation set to identify RSE predictors at SE onset. Their external validity was evaluated with an independent validation set. Measures of calibration and discrimination were assessed. RESULTS: In all, 302 patients were analyzed (138 with and 164 without RSE), 171 in the derivation data set and 131 in the validation data set. Acute SE etiology, coma/stupor and serum albumin <35 g/l at SE onset were independent predictors for RSE in the derivation data set [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.01-4.07; OR 4.83, 95% CI 2.42-9.68; OR 2.45, 95% CI 1.16-5.16]. The prediction model showed good measures of calibration (Hosmer-Lemesow goodness-of-fit test P = 0.99) and discrimination (area under the receiver operating characteristic curve 0.8) on the derivation data set­results that were similar in the validation data set (Hosmer-Lemeshow P = 0.24; area under the receiver operating characteristic curve 0.73). CONCLUSIONS: This study confirms the independent prognostic value of readily available parameters for early RSE prediction. Prospective studies are needed to identify additional robust predictors, which could be added to the proposed model for further optimization towards a reliable prediction scoring system.

Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: a randomized controlled trial.

BACKGROUND: Polio eradication remains a challenge in Pakistan and the causes for the failure to eradicate poliomyelitis are complex. Undernutrition and micronutrient deficiencies, especially zinc deficiency, are major public health problems in Pakistan and could potentially affect the response to enteric vaccines, including oral poliovirus vaccine (OPV). OBJECTIVE: To assess the impact of zinc supplementation among infants on immune response to oral poliovirus vaccine (OPV). METHODS: A double-blind, randomized placebo-controlled trial was conducted in newborns (aged 0-14 days). Subjects were assigned to either receive 10mg of zinc or placebo supplementation daily for 18 weeks. Both groups received OPV doses at birth, at 6 weeks, 10 weeks and 14 weeks. Data was collected on prior immunization status, diarrheal episodes, breastfeeding practices and anthropometric measurements at recruitment and at 6 and 18 weeks. Blood samples were similarly collected to determine the antibody response to OPV and for micronutrient analysis. Logistic regression was used to determine the relationship between seroconversion and zinc status. RESULTS: Overall, 404 subjects were recruited. At recruitment, seropositivity was already high for poliovirus (PV) serotype 1 (zinc: 91.1%; control: 90.5%) and PV2 (90.0%; 92.7%), with lower estimates for PV3 (70.0%; 64.8%). By week 18, the proportion of subjects with measured zinc levels in the normal range (i.e. ≥60 µg/dL) was significantly greater in the intervention group compared to the control group (71.9%; 27.4%; p<0.001). No significant difference in seroconversion was demonstrated between the groups for PV1, PV2, or PV3. CONCLUSIONS: There was no effect of zinc supplementation on OPV immunogenicity. These conclusions were confirmed when restricting the analysis to those with measured higher zinc levels.

[CT and MRI of hip arthroplasty]. / CT und MRT der Hüftprothese.

Metal-induced artifacts impair image quality of computed tomography (CT) and magnetic resonance imaging (MRI) in patients with hip prostheses. Due to new developments in metal artifact reduction both methods can now be used for evaluation of a painful hip prosthesis. Iterative reconstruction algorithms and dual-energy scans are among the newer CT techniques for artifact reduction, while slice-encoding for metal artifact correction (SEMAC) and multi-acquisition variable-resonance image combination (MAVRIC) have introduced substantial improvements for MRI. Loosening of the hip prosthesis, osteolysis from small wear particles and pseudotumors in metal-on-metal prostheses are specific pathologies in patients with total hip arthroplasty. Other causes of painful hip prostheses are infections, fractures, tendinopathies, tendon ruptures, muscle and nerve alterations and heterotopic ossifications.

Electroencephalographic sleep elements and outcome in acute encephalopathic patients: a 4-year cohort study.

BACKGROUND AND PURPOSE: Acute encephalopathy in hospitalized patients is common and associated with high mortality. Preservation of physiological sleep has been associated with favorable outcomes in acute brain injury. It is hypothesized that electroencephalographic presence of sleep elements is associated with good outcome in encephalopathic adults. METHODS: This observational study was performed at an academic tertiary medical care center. Clinical data, electroencephalogram (EEG) characteristics and outcome of critically ill patients with acute encephalopathy were assessed. EEGs were interpreted regarding the presence of sleep elements (K-complexes, vertex sharp-waves and sleep spindles). Associations between sleep elements and outcome (graded by the Glasgow Outcome Scale, GOS) were analyzed. RESULTS: One hundred and forty-two consecutive patients with a median age of 64.5 years (range 18-98) and mean Glasgow Coma Scale 10.4 (± 3.8) were included. Leading etiologies were infections (47.2%), intracranial hemorrhages (14.1%) and ischaemic strokes (10.6%). All EEGs demonstrated encephalopathy patterns and 38% had ≥ 1 sleep element (27.5% K-complexes, 31.7% vertex sharp-waves and 33.8% sleep spindles). Patients without sleep elements were older (P = 0.010) and septic shock was more common (P = 0.014). Amongst sleep elements, K-complexes were significantly associated with good outcome, even after adjusting for possible confounders (odds ratio for GOS 5 = 2.79, 95% confidence interval 1.16-6.69) and without significant effect modification across subgroups. CONCLUSIONS: Whilst EEG sleep elements were detected more frequently in patients with favorable outcome, only K-complexes were significantly and independently associated with good outcome in intensive care unit patients with acute encephalopathy, findings that need to be confirmed in larger prospective studies.

Uncovering clinical and radiological associations of triphasic waves in acute encephalopathy: a case-control study.

BACKGROUND AND PURPOSE: Triphasic waves (TWs) are archetypal waveforms seen on electroencephalography (EEG) in some forms of encephalopathy. Their particular underlying pathological substrates are largely unexplored. This case-control study was designed to identify and quantify specific clinical and neuroradiological associations underlying TWs and to determine if TWs predicate outcome. METHODS: From 2004 to 2012, adult encephalopathic patients with TWs (cases) were matched 1:1 with encephalopathic patients without TWs (controls) by Glasgow Coma Scale (GCS) and the frequency range of EEG background activity. Clinical characteristics, neuroimaging and outcomes were assessed. RESULTS: The mean age of 190 patients (95 with and 95 without TWs) was 66.6 years (±15.6). In multivariable analyses, patients with TWs had significantly higher odds for liver insufficiency [odds ratio (OR) = 8.10, 95% confidence interval (CI) 1.98-33.08], alcohol abuse (OR = 3.65, 95% CI 1.25-10.63), subcortical brain atrophy (OR = 2.82, 95% CI 1.39-5.71) and respiratory tract infections (OR = 1.28, 95% CI 1.01-4.71). With each additional independent predictor, the odds increased for the occurrence of TWs (1 predictor, OR = 2.40, 95% CI 1.16-5.13; ≥2 predictors, OR = 9.20, 95% CI 3.27-25.62). Mortality was 15% and tended to be higher in patients with TWs (19% with vs. 11% without TWs). CONCLUSIONS: Alcohol abuse, liver insufficiency, infections and subcortical brain atrophy were independently associated with TWs in patients matched for clinical and EEG features of encephalopathy. These associations strengthen the hypothesis that TWs evolve from an interplay of pathological neurostructural, metabolic and toxic conditions. When matched for EEG background activity and GCS, TWs were not associated with death.

A study evaluating poliovirus antibodies and risk factors associated with polio seropositivity in low socioeconomic areas of Pakistan.

BACKGROUND: Seroprevalence studies provide important data on performance of immunization programs, susceptible groups and populations at-risk of future outbreaks. Identifying risk factors that affect seroconversion of the oral polio vaccine (OPV) will enable the polio eradication initiatives to increase seroprevalence. This paper describes the first population-based seroprevalence survey in Pakistan. METHODS: This study evaluated the seroprevalence of poliovirus (PV) types 1, 2, and 3 antibodies to OPV in an illustrative sample of 554 subjects 6-11 months of age in three geographic locations of Pakistan (Lahore, Karachi, and Peshawar) representing a low socioeconomic at-risk populations. Antibody titers were measured and sero protection rates and geometric median titers were compared among different geographic regions and populations, as were demographics and OPV vaccination history collected by questionnaire. Univariate and multivariate analyses were conducted on subject characteristics to assess for potential risk factors for failure to sero-convert. RESULTS: The average seroprevalence of PV1, PV2, and PV3 was 96.0%, 87.9% and 86.7%, respectively. The lowest sero protection rate for all three serotypes was for Karachi with 90.2%, 73.8%, and 78.8% for PV1, PV2, and PV3, respectively. Significant regional variation in PV3 seroprevalence was found (range: 74.2-100%). In the univariate analysis, age, total and campaign OPV doses were associated with higher seroprevalence, whereas stunting, respondent education and diarrhea in the past six months were significant risk factors for failure to sero-convert. CONCLUSIONS: These findings demonstrate consistently high levels of antibody response to PV1 and more geographically varied response to PV2 and PV3. Additionally, important risk factors affecting seropositivity were identified.

Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa.

BACKGROUND: Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. METHODS: We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. CONCLUSION: Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team.

Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS.

OBJECTIVE: To describe the diagnosis and management of a 49-year-old woman with multiple sclerosis (MS) developing a progressive hemiparesis and expanding MRI lesion suspicious of progressive multifocal leukoencephalopathy (PML) 19 months after starting natalizumab. RESULTS: Polyomavirus JC (JCV)-specific qPCR in CSF was repeatedly negative, but JCV-specific antibodies indicated intrathecal production. Brain biopsy tissue taken 17 weeks after natalizumab discontinuation and plasmapheresis was positive for JCV DNA with characteristic rearrangements of the noncoding control region, but histology and immunohistochemistry were not informative except for pathologic features compatible with immune reconstitution inflammatory syndrome. A total of 22 months later, the clinical status had returned close to baseline level paralleled by marked improvement of neuroradiologic abnormalities. CONCLUSIONS: This case illustrates diagnostic challenges in the context of incomplete suppression of immune surveillance and the potential of recovery of PML associated with efficient immune function restitution.

Cerebellar stem cells act as medulloblastoma-initiating cells in a mouse model and a neural stem cell signature characterizes a subset of human medulloblastomas.

Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.