Reliability and validity of self-reported questionnaires to measure pain and disability in adults with neck pain and its associated disorders: part 3-a systematic review from the CADRE Collaboration.

PURPOSE: To determine the reliability and validity of self-reported questionnaires to measure pain and disability in adults with grades I-IV neck pain and its associated disorders (NAD). METHODS: We updated the systematic review of the 2000-2010 Bone and Joint Decade Task Force on Neck Pain and its Associated Disorders and systematically searched databases from 2005 to 2017. Independent reviewers screened and critically appraised studies using standardized tools. Evidence from low-risk-of-bias studies was synthesized according to best evidence synthesis principles. Validity studies were ranked according to the Sackett and Haynes classification. RESULTS: We screened 2823 articles, and 26 were eligible for critical appraisal; 18 were low risk of bias. Preliminary evidence suggests that the Neck Disability Index (original and short versions), Whiplash Disability Questionnaire, Neck Pain Driving Index, and ProFitMap-Neck may be valid and reliable to measure disability in patients with NAD. We found preliminary evidence for the validity and reliability of pain measurements including the Body Pain Diagram, Visual Analogue Scale, the Numeric Rating Scale and the Pain-DETECT Questionnaire. CONCLUSION: The evidence supporting the validity and reliability of instruments used to measure pain and disability is preliminary. Further validity studies are needed to confirm the clinical utility of self-reported questionnaires to assess pain and disability in patients with NAD. These slides can be retrieved under Electronic Supplementary Material.

Reliability and validity of clinical tests to assess posture, pain location, and cervical spine mobility in adults with neck pain and its associated disorders: Part 4. A systematic review from the cervical assessment and diagnosis research evaluation (CADRE) collaboration.

PURPOSE: To determine the reliability and validity of clinical tests to assess posture, pain location, and cervical spine mobility in adults with grades I-IV neck pain and associated disorders (NAD). METHODS: We systematically searched electronic databases to update the systematic review of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. Eligible reliability and validity studies were critically appraised using modified versions of the QAREL and QUADAS-2 instruments, respectively. Evidence from low risk of bias studies were synthesized following best evidence synthesis principles. RESULTS: We screened 14302 articles, critically appraised 46 studies, and found 32 low risk of bias articles (14 reliability and 18 validity studies). We found preliminary evidence of: 1) reliability of visual inspection, aided with devices (CROM and digital caliper) to assess head posture; 2) reliability and validity of soft tissue palpation to locate tender/trigger points in muscles; 3) reliability and validity of joint motion palpation to assess stiffness and pain provocation in combination; and 4) range of motion tests using visual estimation (in cervical extension only) or devices (digital caliper, goniometer, inclinometer) to assess cervical mobility. CONCLUSIONS: We found little evidence to support the reliability and validity of clinical tests to assess head posture, pain location and cervical mobility in adults with NAD grades I-III. More advanced validity studies are needed to inform the clinical utility of tests used to evaluate patients with NAD.

Clinical practice guidelines for the noninvasive management of low back pain: A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

We conducted a systematic review of guidelines on the management of low back pain (LBP) to assess their methodological quality and guide care. We synthesized guidelines on the management of LBP published from 2005 to 2014 following best evidence synthesis principles. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane, DARE, National Health Services Economic Evaluation Database, Health Technology Assessment Database, Index to Chiropractic Literature and grey literature. Independent reviewers critically appraised eligible guidelines using AGREE II criteria. We screened 2504 citations; 13 guidelines were eligible for critical appraisal, and 10 had a low risk of bias. According to high-quality guidelines: (1) all patients with acute or chronic LBP should receive education, reassurance and instruction on self-management options; (2) patients with acute LBP should be encouraged to return to activity and may benefit from paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), or spinal manipulation; (3) the management of chronic LBP may include exercise, paracetamol or NSAIDs, manual therapy, acupuncture, and multimodal rehabilitation (combined physical and psychological treatment); and (4) patients with lumbar disc herniation with radiculopathy may benefit from spinal manipulation. Ten guidelines were of high methodological quality, but updating and some methodological improvements are needed. Overall, most guidelines target nonspecific LBP and recommend education, staying active/exercise, manual therapy, and paracetamol or NSAIDs as first-line treatments. The recommendation to use paracetamol for acute LBP is challenged by recent evidence and needs to be revisited. SIGNIFICANCE: Most high-quality guidelines recommend education, staying active/exercise, manual therapy and paracetamol/NSAIDs as first-line treatments for LBP. Recommendation of paracetamol for acute LBP is challenged by recent evidence and needs updating.

Reframing climate change assessments around risk: recommendations for the US National Climate Assessment.

Climate change is a risk management challenge for society, with uncertain but potentially severe outcomes affecting natural and human systems, across generations. Managing climate-related risks will be more difficult without a base of knowledge and practice aimed at identifying and evaluating specific risks, and their likelihood and consequences, as well as potential actions to promote resilience in the face of these risks. We suggest three improvements to the process of conducting climate change assessments to better characterize risk and inform risk management actions.

Elevated incidence of fractures in women with invasive breast cancer.

UNLABELLED: This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy. INTRODUCTION: Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence. METHODS: Retrospective cohort study of women with invasive breast cancer [June 2003-December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR). RESULTS: A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p = 0.03) or history of a prior fracture (6/79, p = 0.004). Fractures occurred 4.0 years (range 0-12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72 + 0.12 g/cm(2), T-score of -1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years. CONCLUSIONS: Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma.

BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival. METHODS: Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma. RESULTS: Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival. CONCLUSIONS: Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.

Splintage in the treatment of sagittal band incompetence and extensor tendon subluxation.

UNLABELLED: This study assessed the success of splintage for traumatic and atraumatic sagittal band incompetence and its relationship to the duration of symptoms before treatment. A retrospective review of all patients with sagittal band incompetence treated with splintage was performed. All patients had extensor tendon subluxation on physical examination. Ninety-two patients were included: 68 traumatic and 24 atraumatic. Subluxation resolved with splintage in 77 patients. Traumatic tendon subluxation resolved in 95% of acute injuries, 100% of subacute injuries, and 67% of chronic injures. Atraumatic tendon subluxation resolved in 100% of patients with acute presentation, 67% of patients with subacute presentation, and 57% of patients with chronic presentation. Surgery was rarely required. Splintage proved very effective for acute sagittal band incompetence, regardless of causation, but decreased in efficiency with chronicity. LEVEL OF EVIDENCE: Level 4.

CD44 promotes Kras-dependent lung adenocarcinoma.

Kras-induced non-small-cell lung adenocarcinoma is the major subtype of lung cancers and is associated with poor prognosis. Using a lung cancer mouse model that expresses a cre-mediated KrasG12D mutant, we identified a critical role for the cell surface molecule CD44 in mediating cell proliferation downstream of oncogenic Kras signaling. The deletion of CD44 attenuates lung adenocarcinoma formation and prolongs the survival of these mice. Mechanistically, CD44 is required for the activation of Kras-mediated signaling through the mitogen-activated protein kinase (MAPK) pathway and thus promotes tumor cell proliferation. Together, these results reveal an unrecognized role for CD44 in oncogenic Kras-induced lung adenocarcinoma and suggest that targeting CD44 could be an effective strategy for halting Kras-dependent carcinomas.

5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype.

Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofetal antigen transcript levels in cytogenetic high-risk subgroups of patients (P<0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P=0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4(+) (Sup5T4) and 5T4(-) (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared with Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4-positive Sup-B15 cells are susceptible to 5T4-specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high-risk pre-B-ALL.

Clinical and immunological response to photodynamic therapy in the treatment of vulval intraepithelial neoplasia.

Vulval intraepithelial neoplasia (VIN) is a premalignant condition of the vulva and its incidence is increasing. The common type of VIN is associated with oncogenic types of human papilloma virus (HPV) infection. The standard modalities of treatment for VIN, surgical excision and laser ablation, are both sub-optimal, associated with high rates of disease recurrence. There is a need for non-surgical treatment options for VIN and photodynamic therapy (PDT), by altering the local immunological parameters, has the potential to clear both VIN and HPV. This article reviews the studies of PDT treatment for VIN and discusses the clinical and immunological responses to PDT treatment in the various studies.

Dose-dependent differential effects of risedronate on gene expression in osteoblasts.

Bisphosphonates have multiple effects on bone. Their actions on osteoclasts lead to inhibition of bone resorption, at least partially through apoptosis. Effects on osteoblasts vary, with modifications in the molecule and concentration both resulting in qualitatively different responses. To understand the mechanism of the differential effects of high and low bisphosphonate concentrations on osteoblast activity, we compared the effects of 10⁻8 M and 10⁻4 M risedronate on gene expression in UMR-106 rat osteoblastic cells. Two targeted arrays, an 84-gene signaling array and an 84-gene osteogeneic array were used. Gene expression was measured at 1 and 24 h. Although some genes were regulated similarly by low and high concentrations of the drug, there was also differential regulation. At 1 h, 11 genes (1 signaling and 10 osteogenesis) were solely regulated by the low concentration, and 7 genes (3 signaling, 4 osteogenesis) were solely regulated by the high concentration. At 24 h, 8 genes (3 signaling, 5 osteogenesis) were solely regulated by the low concentration and 30 genes (16 signaling and 14 osteogenesis) were solely regulated by the high concentration. Interestingly, the low, but not the high concentration of risedronate transiently and selectively upregulated several genes associated with cell differentiation. A number of genes related to apoptosis were regulated, and could be involved in effects of bisphosphonates to promote osteoblast apoptosis. Also, observed gene changes associated with decreased angiogenesis and decreased metastasis could, if they occur in other cell types, provide a basis for the effectiveness of bisphosphonates in the prevention of cancer metastases.

Proximal row carpectomy for scapholunate dissociation.

Thirty-one patients underwent proximal row carpectomy for static scapholunate dissociation without degenerative arthritis. We report the radiographic and clinical results including wrist range of motion, grip strength, use of pain medication, pain severity and patient satisfaction. Mean postoperative flexion/extension was 74° (range 5°-150°) compared with 137° (range 70°-175°) for the uninvolved side. Mean grip strength was 22 kg for the involved side and 39 kg for uninvolved side. Fifteen of 31 patients reported moderate or severe pain after proximal row carpectomy, requiring wrist arthrodesis in four patients. Nearly half of patients involved in manual labour did not return to their pre-injury work status. Our findings suggest that proximal row carpectomy, when performed for static scapholunate dissociation, results in a stiffened, weakened wrist. When compared to historic series involving other treatments for scapholunate dissociation, patients are less likely to return to pre-injury occupation and have subjective and objective parameters that are below normally expected values after proximal row carpectomy performed for other conditions.

Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in osteoblastic cells.

Parathyroid hormone (PTH) is the major hormone regulating bone remodeling. Binding of PTH to the PTH1 receptor (PTH1R), a heterotrimeric G protein coupled receptor (GPCR), can potentially trigger multiple signal transduction pathways mediated through several different G proteins. In this study, we employed G protein antagonist minigenes inhibiting Gα(s), Gα(q) or Gα12 to selectively dissect out which of these G proteins were responsible for effects of PTH(1-34) in targeted signaling and osteogenesis arrays consisting of 159 genes. Among the 32 genes significantly regulated by 24h PTH treatment in UMR-106 osteoblastic cells, 9 genes were exclusively regulated through G(s), 6 genes were solely mediated through G(q), and 3 genes were only controlled through G12. Such findings support the concept that there is some absolute specificity in downstream responses initiated at the G protein level following binding of PTH to the PTH1R. On the other hand, 6 PTH-regulated genes were regulated by both G(s) and G(q), 3 genes were regulated by both G(s) and G12, and 3 genes were controlled by G(s), G(q) and G12. These findings indicate potential overlapping or sequential interactions among different G protein-mediated pathways. In addition, two PTH-regulated genes were not regulated through any of the G proteins examined, suggesting that additional signaling mechanisms may be involved. Selectivity was largely maintained over a 2-48-hour time period. The minigene effects were mimicked by downstream inhibitors. The dissection of the differential effects of multiple G protein pathways on gene regulation provides a more complete understanding of PTH signaling in osteoblastic cells.

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia.

BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure. METHODS: We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed. RESULTS: Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, non-responders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens. CONCLUSION: The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.

Hemi-hamate arthroplasty provides functional reconstruction of acute and chronic proximal interphalangeal fracture-dislocations.

PURPOSE: Hemi-hamate resurfacing arthroplasty is a treatment alternative for the management of severe acute and chronic dorsal proximal interphalangeal (PIP) fracture-dislocations. This study was designed to determine whether this procedure would successfully restore function after such injuries. METHODS: Hemi-hamate reconstructions were performed on 33 patients (mean age, 34 years) who presented to 1 hand surgery practice with dorsal PIP fracture-dislocations. Eligible patients experienced unstable dislocations with comminuted metaphyseal fractures involving at least 50% of the volar middle phalangeal surface that was not amenable to open reduction and internal fixation. We evaluated 22 patients with 14 acute (<6 weeks) and 8 chronic (mean, 30 weeks) injuries at a mean of 4.5 years (range, 1-7 years). Functional outcomes were assessed by objective and subjective measures: joint alignment/motion/stability, grip strength, Disabilities of the Arm, Shoulder, and Hand (DASH) scores, and visual analog scales (VAS) of pain and function. RESULTS: After hemi-hamate reconstruction, active PIP motion averaged 70 degrees (acute 71 degrees , chronic 69 degrees ) with a mean flexion contracture of 19 degrees (range, 0 degrees to 80 degrees ). Active distal interphalangeal motion averaged 54 degrees (acute 56 degrees , chronic 51 degrees ). The mean VAS score for digit pain was 1.4 (acute 0.7, chronic 2.5). The mean DASH score of 5 (acute 2, chronic 9) and VAS functional score of 1.9 (acute 1.4, chronic 2.6) indicated little functional impairment (acute 2, chronic 9). Grip strength averaged 95% of the opposite hand. Mean coronal plane angulation at the PIP joint was 3 degrees . Ten patients reported aching with cold temperatures. One dissatisfied patient underwent revision surgery. Chronic reconstructions were associated with increased VAS pain ratings (p = .02) and higher DASH scores (p = .06). CONCLUSIONS: Hemi-hamate reconstruction represents a valuable surgical procedure to address severe PIP joint fracture-dislocations. Reconstruction of chronic injuries by this method restores PIP function, albeit with more modest outcome performance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

[Analytical methods at the boundary between biochemistry and immunology]. / Vysetrovací metody na pomezí biochemie a imunologie.

The article presents assays shared by both disciplines; i.e the specialization 801 (Clinical Biochemistry) and 813 (Laboratory of Allergology and Immunology), and it covers over 60 tests. It is intended as reference information for general practitioners, as well as for laboratory workers at the beginning of their studies. Emphasis is laid on some facts which GPs ordering laboratory determinations should be familiar with; the pre-analytical stage (specimen collection, their transport and storage), the analytical reliability of particular methods, their accessibility, frequency and total costs. Analytical techniques are only mentioned marginally as their understanding is not essential for GPs. Assuming the readers' fundamental experience of diagnostic applications of the methods discussed; we only comment some obsolete or rare tests. The shared assays cover selected analyses of proteins (incl. some enzymes and tumormarkers), ions, osmolality and quantitative microscopic urinalysis.

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma.

In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.

A specific cadherin phenotype may characterise the disseminating yet non-metastatic behaviour of pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a rare neoplasm of mainly appendiceal origin, characterised by excess intra-abdominal mucin production leading to high morbidity and mortality. While histological features are frequently indolent, this tumour disseminates aggressively throughout the abdominal cavity, yet seldom metastasises. This study determined the expression of several markers of colorectal differentiation (carcinoembryonic antigen (CEA), cytokeratins (CK20 and CK7), epithelial membrane antigen), mucin production (MUC-2, interleukin-9 (IL-9), IL-9 receptor (IL-9Ralpha)), and cell adhesion (N- and E-cadherin, vimentin) in PMP tissue (n=26) compared with expressions in normal colonic mucosa (n=19) and colorectal adenocarcinoma (n=26). Expressions of CEA and cytokeratins were similar for PMP as those in colorectal adenocarcinomas with the exception that the CK20-/CK7- pattern was rare in PMP (Fisher's exact test: P=0.001). Similarly, expressions of mucin-related proteins were comparable for adenocarcinoma and PMP, with the exception that IL-9 expression was uncommon in adenocarcinoma (P=0.009). Pseudomyxoma peritonei demonstrated a specific pattern of adhesion-related protein expressions of increased N-cadherin, reduced E-cadherin, and increased vimentin (P=0.004), a phenotype suggesting a possible epithelial-mesenchymal transition state. Primary PMP cell cultures were successfully maintained and demonstrated marker expressions similar to those seen in in vivo tissues. These early characterisation studies demonstrate similarities between PMP and colorectal adenocarcinoma, but also reveal a specific cadherin phenotype that may characterise the distinct non-metastasising behaviour of PMP, and form the basis for future mechanistic and therapy-targeting research.