Predictors of outcome following an epidural steroid injection for disc-related sciatica: a Delphi consensus study.

PURPOSE: Trial data shows modest reductions in leg pain, disability and surgery avoidance following epidural steroid injections (ESI) for severe sciatica. Despite their common use, there is no clear evidence about which patients are more likely to benefit from ESI. The aim of this study was to generate consensus on potential predictors of outcome following ESI for disc-related sciatica. METHODS: A list of potential predictors of outcome was generated during a consensus meeting of seven experts. The items were subsequently presented in a two round on-line Delphi study to generate consensus among experts on which items are potential predictors of outcome. Consensus was defined as 70% agreement among participants. RESULTS: Sixty-one items were generated during the consensus meeting. Of ninety experts invited to participate in the on-line Delphi study, 44 (48%) and 33 (73%) took part in rounds one and two respectively. Twenty-eight additional items suggested by participants in round one were included in round two. Overall, 14 items reached consensus reflecting domains of health, medication use, pain intensity, psychosocial factors, imaging findings and type of injection. CONCLUSION: Based on expert consensus, items that can be routinely collected in clinical practice were identified as potential predictors of outcomes following ESI.

Improvement in functional outcome 1 year after nonsurgical multidisciplinary treatment for chronic pain after total knee arthroplasty: A prospective cohort study.

PURPOSE: The purpose of this study was to evaluate a multidisciplinary intervention developed for patients with debilitating chronic pain after total knee arthroplasty (TKA) unresponsive to existing treatment options. METHODS: A treatment-based prospective cohort study was caried out in 30 TKA patients with debilitating chronic pain at least 1 year after TKA. The treatment was a multidisciplinary intervention. Main inclusion criteria: no indication for surgery. Primary outcome was function measured by KOOS-PS, OKS, OKS-APQ and WORQ. Secondary outcome measures were pain, fear of movement, self-efficacy, quality of life (QoL), health care and pain medication use, work rehabilitation and patient satisfaction. The assessments took place pre- and directly posttreatment, at 1, 3 and 12 months follow-up. The clinical relevance was assessed by predefined minimal important clinical change (MCIC). RESULTS: At baseline patients were on average 64.7 (±7.9) years old, 67% were female, and they had knee pain for 42 (10-360) months. The results at 12-month follow-up: first, a significant improvement was shown in function, pain, fear of movement, self-efficacy and QoL. Second, in 38.5%-69.2% of patients clinical relevant improvement was shown for functional outcome, 31% for pain, and 50% for self-efficacy. Third, 42% of patients reported 'no healthcare use in the past three months'. CONCLUSION: One year after a multidisciplinary treatment a clinically relevant improvement was shown in terms of function, pain, self-efficacy and QoL. It seems to be a promising treatment option in this difficult-to-treat patient group with debilitating chronic pain after TKA. Future research should examine the effect of the treatment in a larger study population, considering a control group, and focusing on the working population and evaluating cost-efficacy. LEVEL OF EVIDENCE: Level II.

Predictors of outcome in sciatica patients following an epidural steroid injection: the POiSE prospective observational cohort study protocol.

INTRODUCTION: Sciatica can be very painful and, in most cases, is due to pressure on a spinal nerve root from a disc herniation with associated inflammation. For some patients, the pain persists, and one management option is a spinal epidural steroid injection (ESI). The aim of an ESI is to relieve leg pain, improve function and reduce the need for surgery. ESIs work well in some patients but not in others, but we cannot identify these patient subgroups currently. This study aims to identify factors, including patient characteristics, clinical examination and imaging findings, that help in predicting who does well and who does not after an ESI. The overall objective is to develop a prognostic model to support individualised patient and clinical decision-making regarding ESI. METHODS: POiSE is a prospective cohort study of 439 patients with sciatica referred by their clinician for an ESI. Participants will receive weekly text messages until 12 weeks following their ESIand then again at 24 weeks following their ESI to collect data on leg pain severity. Questionnaires will be sent to participants at baseline, 6, 12 and 24 weeks after their ESI to collect data on pain, disability, recovery and additional interventions. The prognosis for the cohort will be described. The primary outcome measure for the prognostic model is leg pain at 6 weeks. Prognostic models will also be developed for secondary outcomes of disability and recovery at 6 weeks and additional interventions at 24 weeks following ESI. Statistical analyses will include multivariable linear and logistic regression with mixed effects model. ETHICS AND DISSEMINATION: The POiSE study has received ethical approval (South Central Berkshire B Research Ethics Committee 21/SC/0257). Dissemination will be guided by our patient and public engagement group and will include scientific publications, conference presentations and social media.

Human Cytomegalovirus Utilizes Multiple Viral Proteins to Regulate the Basement Membrane Protein Nidogen 1.

Nidogen 1 (NID1) is an important basement membrane protein secreted by many cell types. We previously found that human cytomegalovirus (HCMV) infection rapidly induced chromosome 1 breaks and that the basement membrane protein NID1, encoded near the 1q42 break site, was downregulated. We have now determined that the specific breaks in and of themselves did not regulate NID1, rather interactions between several viral proteins and the cellular machinery and DNA regulated NID1. We screened a battery of viral proteins present by 24 hours postinfection (hpi) when regulation was induced, including components of the incoming virion and immediate early (IE) proteins. Adenovirus (Ad) delivery of the tegument proteins pp71 and UL35 and the IE protein IE1 influenced steady-state (ss) NID1 levels. IE1's mechanism of regulation was unclear, while UL35 influenced proteasomal regulation of ss NID1. Real-time quantitative PCR (RT-qPCR) experiments determined that pp71 downregulated NID1 transcription. Surprisingly, WF28-71, a fibroblast clone that expresses minute quantities of pp71, suppressed NID1 transcription as efficiently as HCMV infection, resulting in the near absence of ss NID1. Sequence analysis of the region surrounding the 1q42 break sites and NID1 promoter revealed CCCTC-binding factor (CTCF) binding sites. Chromatin immunoprecipitation experiments determined that pp71 and CTCF were both bound at these two sites during HCMV infection. Expression of pp71 alone replicated this binding. Binding was observed as early as 1 hpi, and colocalization of pp71 and CTCF occurred as quickly as 15 min postinfection (pi) in infected cell nuclei. In fibroblasts where CTCF was knocked down, Adpp71 infection did not decrease NID1 transcription nor ss NID1 protein levels. Our results emphasize another aspect of pp71 activity during infection and identify this viral protein as a key contributor to HCMV's efforts to eliminate NID1. Further, we show, for the first time, direct interaction between pp71 and the cellular genome. IMPORTANCE We have found that human cytomegalovirus (HCMV) utilizes multiple viral proteins in multiple pathways to regulate a ubiquitous cellular basement membrane protein, nidogen-1 (NID1). The extent of the resources and the redundant methods that the virus has evolved to affect this control strongly suggest that its removal provides a life cycle advantage to HCMV. Our discoveries that one of the proteins that HCMV uses to control NID1, pp71, binds directly to the cellular DNA and can exert control when present in vanishingly small quantities may have broad implications in a wide range of infection scenarios. Dysregulation of NID1 in an immunocompetent host is not known to manifest complications during infection; however, in the naive immune system of a developing fetus, disruption of this developmentally critical protein could initiate catastrophic HCMV-induced birth defects.

Non-surgical treatment for adult spinal deformity: results of an intensive combined physical and psychological programme for patients with adult spinal deformity and chronic low back pain-a treatment-based cohort study.

OBJECTIVES: No evidence-based treatment exists for adult spinal deformity (ASD) patients with chronic low back pain (CLBP). AIM OF THIS STUDY: evaluate a combined physical and psychological programme (CPPP) for ASD patients with CLBP and to compare this with a non-ASD-cohort with CLBP. METHODS: Data were extracted from the database of CLBP-patients for whom surgery is not an option and completed CPPP. Two cohorts were selected: an ASD-cohort (n = 80) based on a Cobb angle of > 10° and a consecutive age- and gender-matched non-ASD-cohort (n = 240). PRIMARY OUTCOME: functional status (Oswestry Disability Index; ODI). SECONDARY OUTCOMES: pain intensity, self-efficacy and quality of life. ASSESSMENTS: pre and post treatment, one-month and one-year follow-up (FU). CLINICAL RELEVANCE: minimal important clinical change (MCIC; ODI 10 points), patient acceptable symptom state (PASS; ODI ≤ 22). RESULTS: Demographics ASD-cohort: 79% female, mean age 50.9 (± 14.1) years, mean CLBP duration 15.5 (± 12.5) years, mean Cobb angle 21.4 (± 9.4)°. Non-ASD-cohort: not significantly different. Both cohorts improved in functional status (F[1,318] = 142.982, p < .001; r = 0.31). The ASD-cohort improved from mean ODI 39.5(± 12.0) at baseline to mean ODI 31.8(± 16.5) at one-year FU. CLINICAL RELEVANCE: 51% of the ASD patients reached MCIC and 33% reached a PASS. An interaction effect is shown between time and both cohorts (F[1,318] = 8.2, p = .004; r = 0.03); however, not clinically relevant. All secondary outcomes: improvement at one-year FU. CONCLUSION: This is the first study showing beneficial outcomes of a non-surgical treatment in selected ASD patients with longstanding CLBP. Improvement is shown in functional status, and appeared equivalent to the non-ASD cohort. LEVEL OF EVIDENCE 1: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

A fish with no sex: gonadal and adrenal functions partition between zebrafish NR5A1 co-orthologs.

People with NR5A1 mutations experience testicular dysgenesis, ovotestes, or adrenal insufficiency, but we do not completely understand the origin of this phenotypic diversity. NR5A1 is expressed in gonadal soma precursor cells before expression of the sex-determining gene SRY. Many fish have two co-orthologs of NR5A1 that likely partitioned ancestral gene subfunctions between them. To explore ancestral roles of NR5A1, we knocked out nr5a1a and nr5a1b in zebrafish. Single-cell RNA-seq identified nr5a1a-expressing cells that co-expressed genes for steroid biosynthesis and the chemokine receptor Cxcl12a in 1-day postfertilization (dpf) embryos, as does the mammalian adrenal-gonadal (interrenal-gonadal) primordium. In 2dpf embryos, nr5a1a was expressed stronger in the interrenal-gonadal primordium than in the early hypothalamus but nr5a1b showed the reverse. Adult Leydig cells expressed both ohnologs and granulosa cells expressed nr5a1a stronger than nr5a1b. Mutants for nr5a1a lacked the interrenal, formed incompletely differentiated testes, had no Leydig cells, and grew far larger than normal fish. Mutants for nr5a1b formed a disorganized interrenal and their gonads completely disappeared. All homozygous mutant genotypes lacked secondary sex characteristics, including male breeding tubercles and female sex papillae, and had exceedingly low levels of estradiol, 11-ketotestosterone, and cortisol. RNA-seq showed that at 21dpf, some animals were developing as females and others were not, independent of nr5a1 genotype. By 35dpf, all mutant genotypes greatly under-expressed ovary-biased genes. Because adult nr5a1a mutants form gonads but lack an interrenal and conversely, adult nr5a1b mutants lack a gonad but have an interrenal, the adrenal, and gonadal functions of the ancestral nr5a1 gene partitioned between ohnologs after the teleost genome duplication, likely owing to reciprocal loss of ancestral tissue-specific regulatory elements. Identifying such elements could provide hints to otherwise unexplained cases of Differences in Sex Development.

Human Cytomegalovirus Compromises Development of Cerebral Organoids.

Congenital human cytomegalovirus (HCMV) infection causes a broad spectrum of central and peripheral nervous system disorders, ranging from microcephaly to hearing loss. These ramifications mandate the study of virus-host interactions in neural cells. Neural progenitor cells are permissive for lytic infection. We infected two induced pluripotent stem cell (iPSC) lines and found these more primitive cells to be susceptible to infection but not permissive. Differentiation of infected iPSCs induced de novo expression of viral antigens. iPSCs can be cultured in three dimensions to generate cerebral organoids, closely mimicking in vivo development. Mock- or HCMV-infected iPSCs were subjected to a cerebral organoid generation protocol. HCMV IE1 protein was detected in virus-infected organoids at 52 days postinfection. Absent a significant effect on organoid size, infection induced regions of necrosis and the presence of large vacuoles and cysts. Perhaps more in parallel with the subtler manifestations of HCMV-induced birth defects, infection dramatically altered neurological development of organoids, decreasing the number of developing and fully formed cortical structure sites, with associated changes in the architectural organization and depth of lamination within these structures, and manifesting aberrant expression of the neural marker ß-tubulin III. Our observations parallel published descriptions of infected clinical samples, which often contain only sparse antigen-positive foci yet display areas of focal necrosis and cellular loss, delayed maturation, and abnormal cortical lamination. The parallels between pathologies present in clinical specimens and the highly tractable three-dimensional (3D) organoid system demonstrate the utility of this system in modeling host-virus interactions and HCMV-induced birth defects.IMPORTANCE Human cytomegalovirus (HCMV) is a leading cause of central nervous system birth defects, ranging from microcephaly to hearing impairment. Recent literature has provided descriptions of delayed and abnormal maturation of developing cortical tissue in infected clinical specimens. We have found that infected induced pluripotent stem cells can be differentiated into three-dimensional, viral protein-expressing cerebral organoids. Virus-infected organoids displayed dramatic alterations in development compared to those of mock-infected controls. Development in these organoids closely paralleled observations in HCMV-infected clinical samples. Infection induced regions of necrosis, the presence of larger vacuoles and cysts, changes in the architectural organization of cortical structures, aberrant expression of the neural marker ß-tubulin III, and an overall reduction in numbers of cortical structure sites. We found clear parallels between the pathologies of clinical specimens and virus-infected organoids, demonstrating the utility of this highly tractable system for future investigations of HCMV-induced birth defects.

The absence of p53 during Human Cytomegalovirus infection leads to decreased UL53 expression, disrupting UL50 localization to the inner nuclear membrane, and thereby inhibiting capsid nuclear egress.

Our electron microscopy study (Kuan et al., 2016) found HCMV nuclear capsid egress was significantly reduced in p53 knockout cells (p53KOs), correlating with inhibited formation of infoldings of the inner nuclear membrane (IINMs). Molecular examination of these phenomena has found p53KOs expressed UL97 and phosphorylated lamins, however the lamina failed to remodel. The nuclear egress complex (NEC) protein UL50 was expressed in almost all cells. UL50 re-localized to the inner nuclear membrane (INM) in ~90% of wt cells, but only ~35% of p53KOs. UL53 expression was significantly reduced in p53KOs, and cells lacking UL50 nuclear staining, expressed no UL53. Re-introduction of p53 into p53KOs largely recovered UL53 positivity and UL50 nuclear re-localization. Nuclear rim located UL50/53 puncta, which co-localized with the major capsid protein, were largely absent in p53KOs. We believe these puncta were IINMs. In the absence of p53, UL53 expression was inhibited, disrupting formation of the NEC/IINMs, and reducing functional virion secretion.

Human Cytomegalovirus nuclear egress and secondary envelopment are negatively affected in the absence of cellular p53.

Human Cytomegalovirus (HCMV) infection is compromised in cells lacking p53, a transcription factor that mediates cellular stress responses. In this study we have investigated compromised functional virion production in cells with p53 knocked out (p53KOs). Infectious center assays found most p53KOs released functional virions. Analysis of electron micrographs revealed modestly decreased capsid production in infected p53KOs compared to wt. Substantially fewer p53KOs displayed HCMV-induced infoldings of the inner nuclear membrane (IINMs). In p53KOs, fewer capsids were found in IINMs and in the cytoplasm. The deficit in virus-induced membrane remodeling within the nucleus of p53KOs was mirrored in the cytoplasm, with a disproportionately smaller number of capsids re-enveloped. Reintroduction of p53 substantially recovered these deficits. Overall, the absence of p53 contributed to inhibition of the formation and function of IINMs and re-envelopment of the reduced number of capsids able to reach the cytoplasm.

Development of a triage tool for neurodevelopmental risk in children aged 30 months.

Neurodevelopmental and neuropsychiatric disorders in young children predict educational, health and social problems. Early identification may significantly reduce this burden but relevant tools largely lack validation. We aimed to develop and evaluate the predictive validity of a simple screening tool for neurodevelopmental problems in a community sample of 30 month old children. A sample of children was selected from a community cohort screened at 30 months by health visitors using the Sure Start Language Measure (SSLM) and the Strengths and Difficulties Questionnaire (SDQ) in 2011. Predictive validity was assessed by comparing screening results with detailed psychometric data from the same sample 1-2 years later. Screening performance using different thresholds was explored using Receiver Operating Characteristic (ROC) with ROC area under the curve (AUC) and bootstrapping techniques. The SSLM predicted both language disorder identified by the New Reynell Developmental Language Scales (NRDLS) at follow-up (AUC 0.905) and global developmental delay assessed by the Griffiths Mental Development Scales (AUC 0.983). The SDQ administered at 30 months predicted psychiatric disorders identified by the Development and Wellbeing Assessment (DAWBA) at follow-up (AUC 0.821). Using optimal cut-offs for the SDQ and SSLM at 30 months, both tools together had sensitivity 87%; specificity 64%; positive predictive value 31%; and negative predictive value 97% in the prediction of any kind of neurodevelopmental problem 1-2 years later. The combined measure reported here is not yet sufficient as a stand-alone population screening tool for neurodevelopmental disorders. The SSLM and SDQ did however show promise in identifying preschool children at risk of ongoing language, psychiatric disorders and global developmental delay 1-2 years later but with fairly high false positive rates. Given that current developmental risk prediction in resource-poor settings is little better than random assignment, the SDQ and SSLM may aid clinical judgement when used as interim triage tools for practitioners with no specialist knowledge, in the context of longitudinal follow-up arrangements.

Herniated lumbar disc.

INTRODUCTION: Herniated lumbar disc is a displacement of disc material (nucleus pulposus or annulus fibrosis) beyond the intervertebral disc space. The highest prevalence is among people aged 30 to 50 years, with a male to female ratio of 2:1. There is little evidence to suggest that drug treatments are effective in treating herniated disc. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, non-drug treatments, and surgery for herniated lumbar disc? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 37 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics, antidepressants, bed rest, corticosteroids (epidural injections), cytokine inhibitors (infliximab), discectomy (automated percutaneous, laser, microdiscectomy, standard), exercise therapy, heat, ice, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), percutaneous disc decompression, spinal manipulation, and traction.

Daily functioning and self-management in patients with chronic low back pain after an intensive cognitive behavioral programme for pain management.

Chronic low back pain (CLBP) is associated with persistent or recurrent disability which results in high costs for society. Cognitive behavioral treatments produce clinically relevant benefits for patients with CLBP. Nevertheless, no clear evidence for the most appropriate intervention is yet available. The purpose of this study is to evaluate the mid-term effects of treatment in a cohort of patients with CLBP participating in an intensive pain management programme. The programme provided by RealHealth-Netherlands is based on cognitive behavioral principles and executed in collaboration with orthopedic surgeons. Main outcome parameters were daily functioning (Roland and Morris Disability Questionnaire and Oswestry Disability Questionnaire), self-efficacy (Pain Self-Efficacy Questionnaire) and quality of life (Short Form 36 Physical Component Score). All parameters were measured at baseline, last day of residential programme and at 1 and 12 months follow-up. Repeated measures analysis was applied to examine changes over time. Clinical relevance was examined using minimal clinical important differences (MCID) estimates for main outcomes. To compare results with literature effect sizes (Cohen's d) and Standardized Morbidity Ratios (SMR) were determined. 107 patients with CLBP participated in this programme. Mean scores on outcome measures showed a similar pattern: improvement after residential programme and maintenance of results over time. Effect sizes were 0.9 for functioning, 0.8 for self-efficacy and 1.3 for physical functioning related quality of life. Clinical relevancy: 79% reached MCID on functioning, 53% on self-efficacy and 80% on quality of life. Study results on functioning were found to be 36% better and 2% worse when related to previous research on, respectively, rehabilitation programmes and spinal surgery for similar conditions (SMR 136 and 98%, respectively). The participants of this evidence-based programme learned to manage CLBP, improved in daily functioning and quality of life. The study results are meaningful and comparable with results of spinal surgery and even better than results from less intensive rehabilitation programmes.

Herniated lumbar disc.

INTRODUCTION: Herniated lumbar disc is a displacement of disc material (nucleus pulposus or annulus fibrosis) beyond the intervertebral disc space. The highest prevalence is among people aged 30-50 years, with a male to female ratio of 2:1. There is little evidence to suggest that drug treatments are effective in treating herniated disc. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, non-drug treatments, and surgery for herniated lumbar disc? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics, antidepressants, bed rest, corticosteroids (epidural injections), cytokine inhibitors (infliximab), discectomy (automated percutaneous, laser, microdisectomy, standard), exercise therapy, heat, ice, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), percutaneous disc decompression, spinal manipulation, and traction.

The presence of p53 influences the expression of multiple human cytomegalovirus genes at early times postinfection.

Human cytomegalovirus (HCMV) is a common cause of morbidity and mortality in immunocompromised and immunosuppressed individuals. During infection, HCMV is known to employ host transcription factors to facilitate viral gene expression. To further understand the previously observed delay in viral replication and protein expression in p53 knockout cells, we conducted microarray analyses of p53(+/+) and p53(-/-) immortalized fibroblast cell lines. At a multiplicity of infection (MOI) of 1 at 24 h postinfection (p.i.), the expression of 22 viral genes was affected by the absence of p53. Eleven of these 22 genes (group 1) were examined by real-time reverse transcriptase, or quantitative, PCR (q-PCR). Additionally, five genes previously determined to have p53 bound to their nearest p53-responsive elements (group 2) and three control genes without p53 binding sites in their upstream sequences (group 3) were also examined. At an MOI of 1, >3-fold regulation was found for five group 1 genes. The expression of group 2 and 3 genes was not changed. At an MOI of 5, all genes from group 1 and four of five genes from group 2 were found to be regulated. The expression of control genes from group 3 remained unchanged. A q-PCR time course of four genes revealed that p53 influences viral gene expression most at immediate-early and early times p.i., suggesting a mechanism for the reduced and delayed production of virions in p53(-/-) cells.

Glenohumeral articular cartilage changes in rotator cuff disease.

This study aims to clarify the natural history of glenohumeral articular cartilage changes in rotator cuff disease. We assessed 33 cadaveric shoulder joints, examining the rotator cuffs for macroscopic tears and the articular surfaces for degenerative changes. Ten specimens had tears of the rotator cuff. Articular degenerative changes were noted in 23 joints. Articular cartilage degeneration was almost twice as frequent in the group with rotator cuff tears (10/10 shoulders) as in those without tears (13/23 shoulders). This difference was statistically significant. This strong correlation between tears of the rotator cuff and articular degeneration has not been documented previously, other than in the extreme situation of massive cuff tears and cuff-tear arthropathy. This is deserving of further study because it may have implications for surgical management.