Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy.

Cell therapies are an emergent treatment for cerebral palsy (CP) with promising evidence demonstrating efficacy for improving gross motor function. However, families value improvements in a range of domains following intervention and the non-motor symptoms, comorbidities and complications of CP can potentially be targeted by cell therapies. We conducted a scoping review to describe all outcomes that have been reported in cell therapy studies for CP to date, and to examine what instruments were used to capture these. Through a systematic search we identified 54 studies comprising 2066 participants that were treated with a range of cell therapy interventions. We categorized the reported 53 unique outcome instruments and additional descriptive measures into 10 categories and 12 sub-categories. Movement and Posture was the most frequently reported outcome category, followed by Safety, however Quality of Life, and various prevalent comorbidities and complications of CP were infrequently reported. Notably, many outcome instruments used do not have evaluative properties and thus are not suitable for measuring change following intervention. We provide a number of recommendations to ensure that future trials generate high-quality outcome data that is aligned with the priorities of the CP community.

Persistent Inflammation in Cerebral Palsy: Pathogenic Mediator or Comorbidity? A Scoping Review.

Research has established inflammation in the pathogenesis of brain injury and the risk of developing cerebral palsy (CP). However, it is unclear if inflammation is solely pathogenic and primarily contributes to the acute phase of injury, or if inflammation persists with consequence in CP and may therefore be considered a comorbidity. We conducted a scoping review to identify studies that analyzed inflammatory biomarkers in CP and discuss the role of inflammation in the pathogenesis of CP and/or as a comorbidity. Twelve included studies reported a range of analytes, methods and biomarkers, including indicators of inflammatory status, immune function and genetic changes. The majority of controlled studies concluded that one or more systemic biomarkers of inflammation were significantly different in CP versus controls; most commonly serum or plasma cytokines such as tumor necrosis factor, Interleukin (IL)-6 and IL-10. In addition, differences in inflammation were noted in distinct subgroups of CP (e.g., those with varying severity). The available evidence supports the pathogenic role of inflammation and its ongoing role as a comorbidity of CP. This review shows that inflammation may persist for decades, driving functional impairment across development and into adulthood. However, inflammation is complex, thus further research will increase our understanding.

Do expectations of recovery improve risk assessment for people with whiplash-associated disorders? Secondary analysis of a prospective cohort study.

BACKGROUND: WhipPredict, which includes prognostic factors of pain-related disability, age and hyperarousal symptoms, was developed and validated for prediction of outcome in people with whiplash associated disorders (WAD). Patient expectations of recovery was not an included factor, though is known to mediate outcomes. The aim of this study was to determine whether the addition of expectations of recovery could improve the accuracy of WhipPredict. METHODS: Two hundred twenty-eight participants with acute WAD completed questionnaires (WhipPredict and expectations of recovery) at baseline. Health outcomes (neck disability index (NDI) and Global Perceived Recovery (GPR)) were assessed at 6- and 12-months post injury. Cut-off points for expectations of recovery predictive of both full recovery (NDI ≤10 % , GPR ≥ 4) and poor outcome (NDI ≥30 % , GPR ≤ - 3) were determined, and multivariate logistic regression analyses were used to compare models with and without this variable. RESULTS: Expectations of recovery improved or maintained the accuracy of predictions of poor outcome (6-months: sensitivity 78 to 83%, specificity maintained at 79.5%; 12-months: sensitivity maintained at 80%, specificity 69 to 73%). The sensitivity of predictions of full recovery improved (6-months: 68 to 76%; 12-months: 57 to 81%), though specificity did not change appreciably at 6 months (80 to 81%) and declined at 12 (83 to 76%). ROC curves indicated a larger and more consistent improvement in model performance when expectations of recovery were added to the pathway predictive of full recovery. CONCLUSIONS: The addition of expectations of recovery may improve the accuracy of WhipPredict, though further validation is required.

Clinimetric Properties of Self-reported Disability Scales for Whiplash: A Systematic Review for the Whiplash Core Outcome Set (CATWAD).

OBJECTIVES: A core outcomes set (COS) for whiplash-associated disorders (WADs) has been proposed to improve consistency of outcome reporting in clinical trials. Patient-reported disability was one outcome of interest within this COS. The aim of this review was to identify the most suitable tools for measuring self-reported disability in WAD based on clinimetric performance. METHODS: Database searches took place in 2 stages. The first identified outcome measures used to assess self-reported disability in WAD, and the second identified studies assessing the clinimetric properties of these outcome measures in WAD. Data on the study, population and outcome measure characteristics were extracted, along with clinimetric data. Quality and clinimetric performance were assessed in accordance with the Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN). RESULTS: Of 19,663 records identified in stage 1 searches, 32 were retained following stage 2 searches and screening. Both the Whiplash Disability Questionnaire and Neck Disability Index performed well in reliability (intraclass correlation coefficient=0.84 to 0.98), construct validity (74% to 82% of hypotheses accepted), and responsiveness (majority of correlations in accordance with hypotheses). Both received Category B recommendations due to a lack of evidence for content validity. DISCUSSION: This review identified the Neck Disability Index and Whiplash Disability Questionnaire as the most appropriate patient-reported outcome measures (PROMs) for assessing self-reported disability in WAD based on moderate to high-quality evidence for sufficient reliability, construct validity and responsiveness. However, the content validity of these PROMs has yet to be established in WAD, and until this is undertaken, it is not possible to recommend 1 PROM over the other for inclusion in the WAD COS.

Experiences of responsiveness to exercise in people with chronic whiplash: A qualitative study.

Exercise is recommended in clinical guidelines for the treatment of chronic whiplash associated disorders (WAD). However, randomised controlled trials have shown similar effects for comprehensive exercise programs and advice. To date, there is no clear understanding of why some individuals with WAD appear to respond to exercise whilst others do not. The aim of this study was to explore the experiences and self-reported characteristics of people with chronic whiplash identifying as 'responders' and 'non-responders' to exercise. Semi-structured interviews were conducted with 13 people with chronic whiplash (patients) and seven treating physiotherapists. Patients were asked whether they responded to the exercise program, and what contributed to this. Physiotherapists were asked to share their experiences about the characteristics of people that appear to respond to exercise, and those that do not. An interpretive descriptive approach was selected to facilitate the generation of discipline-specific knowledge. Four themes were generated from patient and physiotherapist interviews, including: (1) the therapeutic relationship, (2) exercise experiences and beliefs, (3) self-efficacy and acceptance, (4) physical and psychological determinants of responsiveness. Responsiveness to exercise is complex and multifaceted. Clinicians may seek to identify the presence of discrete physical impairment(s) (e.g., range of motion restriction), and where present, determine whether targeted exercise results in an immediate and positive response. Clinicians may also focus their efforts on developing aspects of the therapeutic relationship identified as important to patients, such as hope, partnership and rapport.

Defining Recovery in Chronic Whiplash: A Qualitative Study.

OBJECTIVE: The meaning of recovery from musculoskeletal injury is complex, and understanding recovery from whiplash may be particularly important, given the chronic, often recalcitrant nature of the condition. Gaining a better understanding of recovery may also aid in the development and interpretation of future clinical trials. The aim of this study was to define the meaning of recovery from whiplash, and the factors influencing recovery, by exploring the perceptions of people with chronic whiplash, and their treating physiotherapists. MATERIALS AND METHODS: This qualitative study was embedded within a larger randomized-controlled trial, and consisted of semistructured interviews. Interviews were conducted with 13 patient participants with chronic whiplash and 7 physiotherapists. Patient participants were asked what recovery meant to them, and perceptions around barriers and facilitators to recovery were explored. Physiotherapists were also asked to share their beliefs on the meaning of recovery, and what they believe recovery means to their patients. RESULTS: Both patient participants and physiotherapists perceived recovery to be defined within the themes of pain, function, and emotional well-being. Patient participants also identified self-perception as important, whereas physiotherapists identified ownership on the part of the patient, and the multidimensional nature of recovery, including cultural values and beliefs, as important. Several themes relating to barriers and facilitators to recovery were also identified, and included personal and social characteristics and aspects of the therapeutic relationship. DISCUSSION: Recovery is a multidimensional and complex construct. In addition to pain intensity and disability, measurement and conceptualization of recovery should focus on emotional well-being, self-perception, and the cultural values and beliefs of the individual. A positive therapeutic relationship, with attention to psychological and social influences, appears to be important in facilitating recovery and well-being.

Evidence-based care in high- and low-risk groups following whiplash injury: a multi-centre inception cohort study.

BACKGROUND: Studies aimed at improving the provision of evidence-based care (EBC) for the management of acute whiplash injuries have been largely successful. However, whether EBC is broadly provided and whether delivery of EBC varies based on risk of non-recovery, is uncertain. Receiving EBC should improve recovery, though this relationship has yet to be established. Further, mitigating the effect of EBC is the relationship with the practitioner, a phenomenon poorly understood in WAD. This study aimed to determine the proportion of individuals with whiplash, at differing baseline risk levels, receiving EBC. This study also aimed to determine whether receiving EBC and the therapeutic relationship were associated with recovery at 3 months post injury. METHODS: Participants with acute whiplash were recruited from public hospital emergency departments, private physiotherapy practices, and State Insurance Regulatory Authority (SIRA) databases. Participants completed questionnaires at baseline (demographics, risk of non-recovery) and 3-months (treatment received, risk identification, therapeutic relationship) post injury. Primary health care providers (HCPs) treating these participants also completed questionnaires at 3-months. Recovery was defined as neck disability index ≤4/50 and global perceived effect of ≥4/5. RESULTS: Two-hundred and twenty-eight people with acute whiplash, and 53 primary care practitioners were recruited. The majority of the cohort reported receiving EBC, with correct application of the Canadian C-spine rule (74%), and provision of active treatments (e.g. 89% receiving advice) high. Non-recommended (passive) treatments were also received by a large proportion of the cohort (e.g. 50% receiving massage). The therapeutic relationship was associated with higher odds of recovery, which was potentially clinically significant (OR 1.34, 95% CI 1.18-1.62). EBC was not significantly associated with recovery. CONCLUSIONS: Guideline-based knowledge and practice has largely been retained from previous implementation strategies. However, recommendations for routine risk identification and tailored management, and reduction in the provision of passive treatment have not. The therapeutic relationship was identified as one of several important predictors of recovery, suggesting that clinicians must develop rapport and understanding with their patients to improve the likelihood of recovery.

General Exercise Does Not Improve Long-Term Pain and Disability in Individuals With Whiplash-Associated Disorders: A Systematic Review.

Study Design Systematic review of randomized controlled trials. Background General exercise, defined as purposeful physical activity involving repetitive exercises and incorporating multiple muscle groups, is frequently used in the management of whiplash-associated disorders (WADs). Evidence supporting its efficacy is not well established. Objectives To determine whether general exercise is effective in reducing pain and disability in people with WAD. Methods Studies published in English in peer-reviewed journals between January 1990 and May 2015 were eligible if they evaluated a general exercise intervention compared with a different intervention or control. Studies were required to evaluate pain and disability at medium-term (6-14 weeks) and long-term (52 weeks) follow-ups. The mean ± SD and sample size were recorded for follow-up scores and for change scores from baseline to follow-up. Results Of the 3 high-quality studies that were eligible for inclusion, none investigated general exercise alone. There were no clinically meaningful differences between comprehensive exercise programs, which included general exercise, and minimal intervention controls in the medium and long term. No studies directly compared general exercise with a no-treatment control. All included studies used different control interventions, preventing meta-analysis. Conclusion A lack of significant long-term improvements from general exercise interventions in individuals with WAD was identified. This finding differs from the positive benefits of general exercise for other musculoskeletal conditions. This may, in part, relate to the complexity of whiplash conditions. This may also reflect the challenge of exercise prescription in this population, where the need for sufficient intensity is balanced against the impact that exercise has on pain. Level of Evidence Therapy, level 1a. J Orthop Sports Phys Ther 2017;47(7):472-480. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7081.

Risk factors for low back pain: insights from a novel case-control twin study.

BACKGROUND CONTEXT: Previous research has failed to identify strong consistent risk factors for low back pain (LBP). A plausible solution is to conduct hypothesis-generating studies, such as twin case-control surveys. PURPOSE: To investigate twins' perceptions of the factors responsible for within-pair differences in LBP. STUDY DESIGN: A case-control twin survey. PATIENT SAMPLE: Twenty-four twin pairs that were generally and broadly discordant for LBP history. OUTCOME MEASURES: The participants' perceptions of the factors that could explain within-pair differences in LBP history. METHODS: Twins were asked to identify the factors responsible for within-pair differences in LBP. Closed questioning collected information on the known risk factors and open-ended questioning was used to reveal novel factors. The frequency of risk factors was presented to investigate the individual's perception of the contribution of factors in the development of their own and/or their twin's experience of LBP. RESULTS: The most frequent factors reported in the closed questioning related to the physical workload of the lumbar spine, specifically, the engagement in different types of work (n=23/24 pairs, 96%). Types of work included those involving heavy loads, lifting, manual tasks, awkward postures, and gardening. Single trauma or injury and vigorous physical activity participation were perceived as the contributors by 79% (n=19/24 pairs) and 88% (n=21/24 pairs) of the pairs, respectively. Open-ended questioning did not reveal new risk factors for LBP. CONCLUSIONS: Twins attributed the differences in LBP history to risk factors related to physical workload. Future studies investigating the risk factors for LBP should include valid and comprehensive assessments of these factors.

Lanthanum tetrazinc, LaZn4.

The structure of lanthanum tetrazinc, LaZn(4), has been determined from single-crystal X-ray diffraction data for the first time, approximately 70 years after its discovery. The compound exhibits a new structure type in the space group Cmcm, with one La atom and two Zn atoms occupying sites with m2m symmetry, and one Zn atom occupying a site with 2.. symmetry. The structure is closely related to the BaAl(4), La(3)Al(11), BaNi(2)Si(2) and CaCu(5) structure types, which can be presented as close-packed arrangements of 18-vertex clusters, in this case LaZn(18). The kindred structure types contain related 18-vertex clusters around atoms of the rare earth or alkaline earth metal.

Photocrystallographic identification of metastable nitrito linkage isomers in a series of nickel(II) complexes.

Single crystal photocrystallographic experiments and solid state Raman spectroscopy have been used to determine the low temperature, metastable structures of the nickel(ii) nitrito complexes [Ni(aep)(2)(η(1)-ONO)(2)] 1#O (aep = 1-(2-aminoethyl)piperidine), [Ni(aem)(2)(η(1)-ONO)(2)] 2#O (aem = 1-(2-aminoethyl)morpholine), and [Ni(aepy)(2)(η(1)-ONO)(2)] 3#O (aepy = 1-(2-aminoethyl)pyrrolidine and where the #O denotes the oxygen-bound nitrito metastable molecule). These linkage isomers of the equivalent nitro complexes [Ni(aep)(2)(η(1)-NO(2))(2)] 1, [Ni(aem)(2)(η(1)-NO(2))(2)] 2 and [Ni(aepy)(2)(η(1)-NO(2))(2)] 3 are formed by LED irradiation at temperatures below 120 K. The behavior of the three complexes upon irradiation is generally similar, but some subtle differences have been observed. From the crystallographic studies all three complexes 1-3 exhibit the endo-nitrito linkage isomer upon irradiation, however, for 3# (a crystal structure that contains components of both 3 and 3#O) an exo-nitrito isomer is also observed. Under conditions of 90-100 K, with blue light, the conversion percentages to the nitrito isomers, 1#O, 2#O and 3#O were 16%, 22% and 30%, respectively. At temperatures below 110 K all three nitrito isomers were stable for over four hours but while 2#O and 3#O could be detected at temperatures down to 30 K, at temperatures below 60 K the metastable structure 1#O appeared to be quenched and only the nitro isomer 1 was identified in the crystal. The solid state Raman spectra for 1#, 2# and 3# confirmed the photocrystallographic results with the nitrito isomers being identified from the O-N-O deformation vibrations.