The risk of delayed spinal cord injury in pediatric spinal deformity surgery.

Delayed spinal cord injury (SCI) hours or days after surgery, with uneventful monitoring and initial normal postoperative neurological examination, is a rare complication. Based on anecdotal evidence, the risk of delayed spinal cord injury might be higher than previously assumed. Therefore the aim of this study was to determine the risk of delayed SCI after pediatric spinal deformity surgery between 2013-2019 in the Netherlands. The total number of pediatric spinal deformity surgeries performed for scoliosis or kyphosis between 2013-2019 was obtained from the Dutch National Registration of Hospital Care. All eleven Dutch hospitals that perform pediatric spinal deformity surgery were contacted for occurrence of delayed SCI. From the identified patients with delayed SCI, the following data were collected: patient characteristics, details about the SCI, the surgical procedure, management and degree of improvement.2884 pediatric deformity surgeries were identified between 2013-2019. Seven patients (0.24%) with delayed SCI were reported: 3 idiopathic, 2 neuromuscular (including 1 kypho-scoliosis) and 2 syndromic scoliosis. The risk of delayed SCI after pediatric deformity surgery was 1:595 in idiopathic scoliosis, 1:214 in syndromic scoliosis, 1:201 in neuromuscular scoliosis. All seven patients had a documented normal neurological examination in the first postoperative period; neurological deficits were first diagnosed at a median 16h (range 2.5-40) after surgery. The risk of delayed SCI after pediatric deformity surgery is higher than previously reported, especially in patients with non-idiopathic scoliosis. Regular postoperative testing for late neurologic deficit should be performed for timely diagnosis and management of this devastating complication.

Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

Approaches towards optimising the gamma interferon assay for diagnosing Mycobacterium bovis infection in African buffalo (Syncerus caffer).

The application of diagnostic tests for bovine tuberculosis in wildlife poses formidable technical difficulties and the use of the gamma interferon assay offers a simplified approach to testing wild animal species. We compared the performance of the gamma interferon assay in African buffalo (Syncerus caffer) under the recommended guidelines for interpretation of test results and found a high sensitivity (92.1%) at the cost of a greatly reduced specificity (68.3%). The optimised cut-off value for positive test results under local conditions was identified at an optical density of 0.385 at wavelength 450nm as the preferred compromise between sensitivity and specificity. Additional optimisation approaches to improve test performance were examined and showed that the application of 'a priori exclusions' of test results on the basis of reactivity to fortuitum PPD (sensitin produced from Mycobacterium fortuitum) and to a lesser degree, avian PPD, increased specificity without losing sensitivity. The implications of these findings on a modified testing protocol adjusted to include measurement of immune responsiveness to fortuitum PPD and other interpretation schemes are discussed.

Zoonotic tuberculosis and brucellosis in Africa: neglected zoonoses or minor public-health issues? The outcomes of a multi-disciplinary workshop.

Late in 2007, veterinary, medical and anthropological professionals from Europe and Africa met in a 2-day workshop in Pretoria, South Africa, to evaluate the burden, surveillance and control of zoonotic tuberculosis and brucellosis in sub-Saharan Africa. Keynote presentations reviewed the burden of these diseases on human and livestock health, the existing diagnostic tools, and the available control methods. These presentations were followed by group discussions and the formulation of recommendations. The presence of Mycobacterium bovis and Brucella spp. in livestock was considered to be a serious threat to public health, since livestock and animal products are the only source of such infections in human beings. The impact of these pathogens on human health appears to be relatively marginal, however, when compared with Mycobacterium tuberculosis infections and drug resistance, HIV and malaria. Appropriate diagnostic tools are needed to improve the detection of M. bovis and Brucella spp. in humans. In livestock, the 'test-and-slaughter' approach and the pasteurization of milk, which have been used successfully in industrialized countries, might not be the optimal control tools in Africa. Control strategies should fit the needs and perceptions of local communities. Improved intersectoral and international collaboration in surveillance, diagnosis and control, and in the education of medical and veterinary personnel, are advocated.

Surgeon equipoise as an inclusion criterion for the evaluation of nonoperative versus operative treatment of thoracolumbar spinal injuries.

BACKGROUND CONTEXT: Prospective studies have failed to demonstrate the superiority of either operative or nonoperative treatment of thoracolumbar fractures. Similar to other surgical fields, research has been limited by the variability in surgical interventions, difficult recruitment, infrequent pathology, and the urgency of interventions. PURPOSE: To outline factors precluding randomized controlled trials in spinal fractures research, and describe a novel methodology that seeks to improve on the design of observational studies. STUDY DESIGN/SETTING: A preliminary report describing an observational study design with clinical equipoise as an inclusion criterion. The proposed methodology is a cohort study with head-to-head comparison of operative and nonoperative treatment regimens in an expertise-based trial fashion. Patients are selected retrospectively by an expert panel and clinical outcomes are assessed to compare competing treatment regimens. Surgeon equipoise served as an inclusion criterion. PATIENT SAMPLE: Patients with closed or open thoracolumbar spinal fracture with or without neurological impairment, presenting to one of two different trauma centers between 1991 and 2005 (N = 760). OUTCOME MEASURES: Homogeneity of baseline clinical and demographic data and distribution of prognostic risk factors between the operative and the nonoperative cohort. METHODS: Patients treated for spine fractures at two University hospitals practicing opposing methods of fracture intervention were identified by medical diagnosis code searches (n = 760). A panel of spine treatment experts, blinded to the treatment received clinically has assessed each case retrospectively. Patients were included in the study when there was disagreement on the preferred treatment, that is, operative or nonoperative treatment of the injury. Baseline and initial data of a study evaluating nonoperative versus operative spinal fracture treatment are presented. RESULTS: One hundred and ninety patients were included in the study accounting for a panel discordance rate of 29%. The distribution of baseline characteristics and demographics of the study populations were equal across the parallel cohorts enrolled in the study, that is, no differences in prognostic factors were observed. CONCLUSIONS: The use of clinical equipoise as an inclusion criterion in comparative studies may be used to avoid selection bias. Using multivariate analysis of retrospectively assembled parallel cohorts, a valid comparison of operative and nonoperative spine fracture treatment strategies and their outcomes is possible.

Scoliosis in Prader-Willi syndrome: prevalence, effects of age, gender, body mass index, lean body mass and genotype.

BACKGROUND: The reported prevalence of scoliosis in children with Prader-Willi syndrome varies from 15% to 86%. OBJECTIVE: To study the prevalence of scoliosis and the effects of age, gender, body mass index (BMI), total lean body mass (LBM), LBM of the trunk (trunkLBM) and genotype. DESIGN: Radiographs were taken, length and weight were measured (BMI standard deviation scores (BMI SDS) and body surface area (BSA)), and dual energy x-ray absorptiometry was performed, measuring LBM and trunkLBM. PATIENTS: 96 children, median (interquartile range) age 4.8 years (2.1 to 7.5), were included in a multicentre study. None received growth hormone treatment. MAIN OUTCOME MEASURES: Two types of scoliosis were identified: (1) long C-curve type scoliosis (LCS) and (2) idiopathic scoliosis (IS). Children were divided into age categories (infants, 0-3 years; juveniles, 3-10 years; adolescents, 10-16 years). RESULTS: The prevalence of scoliosis was 37.5% and increased with age (infants and juveniles, approximately 30%; adolescents, 80%); 44% of children with scoliosis had a Cobb angle above 20 degrees . Children with scoliosis were significantly older than those without. Children with LCS were younger and more hypotonic than those with IS: median (interquartile range) age 4.4 years (1.7-5.9) vs 11.1 years (6.5-12.1) (p = 0.002) and trunkLBM/BSA ratio 7080 (6745-7571) vs 7830 (6932-8157) (p = 0.043). CONCLUSIONS: The prevalence of scoliosis in children with Prader-Willi syndrome is high (37.5%). Many children with scoliosis (13%) had undergone brace treatment or surgery. The type of scoliosis is affected by age and trunkLBM/BSA ratio.

Characterisation of a SAT-1 outbreak of foot-and-mouth disease in captive African buffalo (Syncerus caffer): clinical symptoms, genetic characterisation and phylogenetic comparison of outbreak isolates.

African buffalo (Syncerus caffer) play an important role in the maintenance of the SAT types of foot-and-mouth disease (FMD) in southern Africa. These long-term carriers mostly become sub-clinically infected, maintaining the disease and posing a threat to other susceptible wildlife and domestic species. During an unrelated bovine tuberculosis experiment using captive buffalo in the Kruger National Park (KNP), an outbreak of SAT-1 occurred and was further investigated. The clinical signs were recorded and all animals demonstrated significant weight loss and lymphopenia that lasted 100 days. In addition, the mean cell volume and mean cell haemoglobin values were significantly higher than before the outbreak started. Virus was isolated from several buffalo over a period of 167 days post infection and the molecular clock estimated to be 3 x 10(-5) nucleotide substitutions per site per day. Seven amino acid changes occurred of which four occurred in hypervariable regions previously described for SAT-1. The genetic relationship of the outbreak virus was compared to buffalo viruses previously obtained from the KNP but the phylogeny was largely unresolved, therefore the relationship of this outbreak strain to others isolated from the KNP remains unclear.

An experimental intratonsilar infection model for bovine tuberculosis in African buffaloes, Syncerus caffer.

An infection model for Mycobacterium bovis in African buffaloes, Syncerus caffer, was developed, using the intratonsilar route of inoculation. Two groups of 11 buffaloes each, aged approximately 18 months, were infected with either 3.2 x 10(2) cfu (low dose) or 3 x 10(4) cfu (high dose) of M. bovis strain isolated from a buffalo. A control group of six buffaloes received saline via the same route. The infection status was monitored in vivo using the comparative intradermal tuberculin test, and in vitro by the modified interferon-gamma assay. All buffaloes were euthanazed 22 weeks post infection and lesion development was assessed by macroscopic examination, culture and histopathology. It was found that the high dose caused macroscopic lesions in nine out of 11 buffaloes. Mycobacterium bovis was isolated from all buffaloes in the high-dose group and from six out of 11 in the low-dose group.

Spontaneous remodeling of the spinal canal after conservative management of thoracolumbar burst fractures.

STUDY DESIGN: Forty-two conservatively treated patients with a burst fracture of the thoracic, thoracolumbar, or lumbar spine with more than 25% stenosis of the spinal canal were reviewed more than 1 year after injury to investigate spontaneous remodeling of the spinal canal. OBJECTIVES: To investigate the natural development of the changes in the spinal canal after thoracolumbar burst fractures. SUMMARY OF THE BACKGROUND DATA: Surgical removal of bony fragments from the spinal canal may restore the shape of the spinal canal after burst fractures. However, it was reported that restoration of the spinal canal does not affect the extent of neurologic recovery. METHODS: Using computerized tomography, the authors compared the least sagittal diameter of the spinal canal at the time of injury with the least sagittal diameter at the follow-up examination. RESULTS: Remodeling and reconstitution of the spinal canal takes place within the first 12 months after injury. The mean percentage of the sagittal diameter of the spinal canal was 50% of the normal diameter (50% stenosis) at the time of the fracture and 75% of the normal diameter (25% stenosis) at the follow-up examination. The correlation was positive between the increase in the sagittal diameter of the spinal canal and the initial percentage stenosis. There was a negative correlation between the increase in the sagittal diameter of the spinal canal and age at time of injury. Remodeling of the spinal canal was not influenced by the presence of a neurologic deficit. CONCLUSION: Conservative management of thoracolumbar burst fractures is followed by a marked degree of spontaneous redevelopment of the deformed spinal canal. Therefore, this study provides a new argument in favor of the conservative management of thoracolumbar burst fractures.

Peroneus longus and tibialis anterior muscle activity in the stance phase. A quantified electromyographic study of 10 controls and 25 patients with chronic ankle instability.

The electromyographic activity of the peroneus longus and anterior tibial muscles of 25 patients with chronic ankle instability (18 patients with bilateral symptoms and 7 patients with unilateral complaints) and 10 controls was registered during the stance phase under different walking conditions. With balance secured by external support, there was a variable amount of peroneal activity, most of which was found in the third quarter of stance. A high increase in peroneus longus activity starting after foot-flat was found when subjects had to maintain balance in a natural way. No difference in peroneal activity was found in relation to instability complaints. It is thought that the peroneus longus serves to maintain balance, that this function decreases with increase of speed and that one cannot rely on this muscle to prevent an inversion injury during normal walking. The anterior tibial muscle was predominantly active in the first quarter after heel contact. An increase in activity in the second quarter as an effect of loss of secured balance suggests that this muscle plays some part in balance control, but this is not its main function. A significant increase in tibialis anterior activity was found in patients with bilateral instability. No significant difference was found between the symptomatic and asymptomatic leg of patients with unilateral instability under the same walking conditions. These findings suggest changes in central control.

Recurrent kyphosis after posterior stabilization of thoracolumbar fractures. 24 cases treated with a Dick internal fixator followed for 1.5-4 years.

24 patients with Th12-L1 fractures treated with a Dick internal fixator were analyzed to assess predictors of poor outcome. 4 patients had fixation without bone transplantation, 20 patients had a posterior fusion, and 12 of them had additional transpedicular spongioplasty. There were fractures of the transpedicular screws in 4 and screw migration in 2 cases. The increase in the local kyphosis angle was greater than the increase in the anterior compression angle and this did not correlate with spongioplasty or fusion. Fixation failure was in all cases related to a disproportionate increase in the local kyphosis angle. There was no difference between the patients with transpedicular spongioplasty and posterior fusion and the other patients with respect to results and complications. Bony collapse was not the major cause of failure and consequently there was no measureable contribution of transpedicular spongioplasty. We found that the Dick internal fixator for unstable fractures was associated with a higher complication rate than earlier reported.

CT scan prediction of neurological deficit in thoracolumbar burst fractures.

In 139 patients with burst fractures of the thoracic, thoracolumbar or lumbar spine, the least sagittal diameter of the spinal canal at the level of injury was measured by computerised tomography. By multiple logistic regression we investigated the joint correlation of the level of the burst fracture and the percentage of spinal canal stenosis with the probability of an associated neurological deficit. There was a very significant correlation between neurological deficit and the percentage of spinal canal stenosis; the higher the level of injury the greater was the probability. The severity of neurological deficit could not be predicted.

Homosexual and heterosexual partner preference in ovariectomized female rats: effects of testosterone, estradiol and mating experience.

Ovariectomized female rats, longterm treated with estradiol benzoate (EB, 20 micrograms, 3 x/week) or testosterone propionate (TP, 0.4 mg, 3 X/week), were tested for homo- or heterosexual partner preference behavior with either tethered animals (sexually active male vs. estrous female) or animals behind a wire mesh. A preference score was calculated by subtracting the time spent in the vicinity of the stimulus female from the time spent in the vicinity of the stimulus male. Thus, a positive score indicates preference for the male (heterosexual preference), a negative score preference for the female (homosexual preference). Two weeks of EB treatment caused a clearcut preference for the male incentive. This heterosexual preference was significantly different from the indistinct preference of the TP-treated females. Sexual interaction with a freely moving active male (with or without a vaginal mask which prevented intromissions) did not alter the preference for the male of the EB-treated females. It did affect, however, the preference behavior of the TP-treated females significantly: it changed in the direction of the sexually active estrous incentive female, i.e., a homosexual preference. This change in preference could not be attributed to the experience of penile intromissions, it occurred despite the presence of a vaginal mask. Apparently, being mounted by a sexually active male had a negative reinforcing value in the TP-treated female rats and provoked a homosexual partner preference.