AAV gene delivery to the spinal cord: serotypes,methods, candidate diseases,and clinical trials

Introduction: Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders – spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) – are now underway.

Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed.

Expert opinion: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

Content and bibliometric analyses of the Journal of Manual & Manipulative Therapy

Background:

Article characteristics and trends have been elucidated for other physical therapy-focused journals using content and bibliometric analysis. These findings are important for assessing the current state of a journal and for guiding future publication of research. To date, these analyses have not been performed for the Journal of Manual & Manipulative Therapy (JMMT).

Objective:

To describe content and trends for articles published in JMMT over a 20-year period (1993–2012).

Methods:

Journal articles were coded using previously-established domains (article type, participant type, research design, study purpose, and clinical condition). Total publications and proportion of publications based on domain were described. Articles specific to manual therapy intervention were examined and compared to data from other physical therapy-focused journals. Impact by citation and author was examined using bibliometric software.

Results:

Journal of Manual & Manipulative Therapy was found to have a recent acceleration in the number of articles published annually. Over time, topical reviews have decreased in favor of research reports. However, rigorous study designs have represented only a small portion of total journal content, and case reports have maintained a consistent publication presence. Manual therapy intervention articles in JMMT are predominantly case designs, however are similar in characteristics to manual therapy intervention articles published in other physical therapy-focused journals. For JMMT articles overall and manual therapy intervention articles across journals, young to middle-aged symptomatic adults with low back and/or neck pain were the most common study participants.

Discussion:

Increases in the number of papers and a move toward research reports were observed in JMMT over the 20-year period. Considerations for the future were outlined, including the publication of articles with more rigorous research designs. Manual therapy research for adolescents and older adults and for upper and lower extremity conditions should also be considered as priorities for the future.     

Gene therapy for age-related macular degeneration

Introduction: In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with ‘real world’ undertreatment.

Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD.

Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.     

Effect of changing from first- to second-line antiretroviral therapy on renal function: a retrospective study based on data from a single health facility in Namibia

Background: Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. As a result, the aim of this study is to assess effects of second-line cART on renal function.

Methods: Retrospective longitudinal study in patients receiving cART.

Results: 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART. Time spent on cART weak had a week relationship with CrCl.

Conclusion: Patients on first-line cART for several years without renal impairment may experience new onset impairment during second line cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

Subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder manual therapy plus exercise intervention in individuals with subacromial impingement syndrome: a prospective,randomized controlled clinical trial pilot study

Objectives: To determine the subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder non-thrust plus exercise in patients with subacromial pathology.

Methods: This was a randomized, single blinded controlled trial pilot study. This trial was registered at ClinicalTrials.gov (NCT01753271) and reported according to Consolidated Standards of Reporting Trials requirements. Patients were randomly assigned to either shoulder treatment plus cervicothoracic spinal thrust/non-thrust or shoulder treatment-only group. Primary outcomes were average pain intensity (Numeric Pain Rating Scale) and physical function (Shoulder Pain and Disability Index) at 2 weeks, 4 weeks, and patient discharge.

Results: 18 patients, mean age 43.1(15.8) years satisfied the eligibility criteria and were analyzed for follow-up data. Both groups showed statistically significant improvements in both pain and function at 2 weeks, 4 weeks, and discharge. The between-group differences for changes in pain or physical function were not significant at any time point.

Discussion: The addition of cervicothoracic spinal thrust/non-thrust to the shoulder treatment-only group did not significantly alter improvement in pain or function in patients with subacromial pathology. Both approaches appeared to provide an equally notable benefit. Both groups improved on all outcomes and met the criteria for clinical relevance for both pain and function.

Level of Evidence: 2b.     

Gene-based therapies in patients with critical limb ischemia

Introduction: Critical limb ischemia (CLI) constitutes a life-limiting and life-threatening disease. Revascularization, either endovascular or surgical, remains the best treatment option accompanied by medication and risk factor modification. Patients unable to undergo revascularization, referred as ‘no-option patients’, have been the center of interest the last few years, subjected to treatment therapies based on proteins (mainly growth factors) involved in angiogenesis via gene delivery to the ischemic tissue.

Areas covered: This review focuses on these growth factors, gives an update of the studies available, discusses the possible problems that influence outcomes and describes future perspectives including possible new technologies that will improve them. Additionally, the authors attempt to place therapeutic angiogenesis to the bigger frame of tailored therapy in CLI.

Expert opinion: Although encouraging in the beginning, growth factor therapy results have been equivocal and inconclusive. And while it would be misleading to approach gene therapy as panacea, its effect on the micro-circulatory level activating angiogenesis and arteriogenesis could act as an important adjunct in personalized treatment.     

Thrust joint manipulation utilization by U.S. physical therapists*

Study Design: Online survey study.

Objective: To determine physical therapists’ utilization of thrust joint manipulation (TJM) and their comfort level in using TJM between the cervical, thoracic, and lumbar regions of the spine. We hypothesized that physical therapists who use TJM would report regular use and comfort providing it to the thoracic and lumbar spines, but not so much for the cervical spine.

Background: Recent surveys of first professional physical therapy degree programs have found that TJM to the cervical spine is not taught to the same degree as to the thoracic and lumbar spines.

Methods: We developed a survey to capture the required information and had a Delphi panel of 15 expert orthopedic physical therapists review it and provide constructive feedback. A revised version of the survey was sent to the same Delphi panel and consensus was obtained on the final survey instrument. The revised survey was made available to any licensed physical therapists in the U.S.A. using an online survey system, from October 2014 through June 2015.

Results: Of 1014 responses collected, 1000 completed surveys were included for analysis. There were 478 (48%) males; the mean age of respondents was 39.7 ± 10.81 years (range 24–92); and mean years of clinical experience was 13.6 ± 10.62. A majority of respondents felt that TJM was safe and effective when applied to lumbar (90.5%) and thoracic (91.1%) spines; however, a smaller percentage (68.9%) felt that about the cervical spine. More therapists reported they would perform additional screening prior to providing TJM to the cervical spine than they would for the lumbar and thoracic spines. Therapists agreed they were less likely to provide and feel comfortable with TJM in the cervical spine compared to the thoracic and lumbar spines. Finally, therapists who are male; practice in orthopedic spine setting; are aware of manipulation clinical prediction rules; and have manual therapy certification, are more likely to use TJM and be comfortable with it in all three regions.

Conclusion: Results indicate that respondents do not believe TJM for the cervical spine to be as safe and efficacious as that for the lumbar and thoracic spines. Further, they are more likely to perform additional screening, abstain from and do not feel comfortable performing TJM for the cervical spine.

Clinical Relevance: Our research reveals there is a discrepancy between utilization of TJM at different spinal levels. This research provides an opportunity to address variability in clinical practice among physical therapists utilizing TJM.     

Management of ventilator-associated pneumonia: Need for a personalized approach

Introduction: Optimizing management of ventilator-associated pneumonia (VAP) should focus on the accurate identification of true lung infection, determination of the etiological agent, and early institution of adequate empirical therapy and de-escalation. Local adaptation of the standard guidelines leads to favorable outcome in the management of VAP

Areas covered: In this review, we present the concepts of early adequate therapy and the key considerations such as patient characters, clinical and etiological diagnosis, and assessment of patients for de-escalation that favor optimization of therapy. We highlight the issues that need a personalized approach in the management of VAP emphasizing on various patient categories for reassessment and tailoring the therapy.

Expert commentary: Rapid diagnostic techniques and non-invasive metabolomics will identify phenotypes which will shift the traditional paradigm based on conventional cultures. A personalized approach taking into account baseline resistance epidemiology, underlying disease (and comorbidities), duration of hospitalization, and prior antimicrobial exposure should guide targeted therapy.     

Factors influencing physical therapists’ clinical reasoning: qualitative systematic review and meta-synthesis

Background: The capacity of physical therapists to reason effectively in patient management is essential to maximizing outcomes. Although conceptual frameworks of clinical reasoning exist, their theoretical foundations are insufficiently validated to establish those factors that are paramount in guiding physical therapists’ clinical reasoning. Studies on how physical therapists clinically reason constitute important means of identifying constructs of such reasoning.

Objective: This systematic review aimed to synthesize and interpret the findings of qualitative studies designed to examine factors that are inherent in physical therapists’ clinical reasoning with respect to their knowledge, experiences, and practices.

Methods: Searches of studies were carried out in four databases, gray literature, and reference lists. Two reviewers independently assessed methodological quality of the studies using the Critical Appraisal Skills Program (CASP) and performed the analysis: extraction and comparative appraisal of findings, identification of themes, reciprocal translation synthesis, and identification of categories and subcategories.

Results: Ten studies were included. Four themes of factors influencing physical therapists’ clinical reasoning emerged, namely, Physical therapist as a source, Patient as a source, Elements of the reasoning process, and Context.

Conclusions: The identified themes validated some constructs underlying existing clinical reasoning frameworks. Most influencing factors were related to the physical therapist, which highlights opportunities to improve effective reasoning at this level. The notion that this process is recurrent, multifaceted, and contextual lends itself to changing in accordance with the needs of the patient, consistent with a biopsychosocial perspective. How clinicians weigh biomedical and psychosocial elements in their reasoning however warrants further study.     

Adeno-Associated Virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments

Introduction: Since the cystic fibrosis (CF) gene was discovered in 1989, researchers have worked to develop a gene therapy. One of the most promising and enduring vectors is the AAV, which has been shown to be safe. In particular, several clinical trials have been conducted with AAV serotype 2. All of them detected viral genomes, but identification of mRNA transduction was not consistent; clinical outcomes in Phase II studies were also inconsistent. The lack of a positive outcome has been attributed to a less-than-efficient viral infection by AAV2, a weak transgene promoter and the host immune response to the vector.

Areas covered: Herein, the authors focus on AAV gene therapy for CF, evaluating past experience with this approach and identifying ways forward, based on the progress that has already been made in identifying and overcoming the limitations of AAV gene therapy.

Expert opinion: Such progress makes it clear that this is an opportune time to push forward toward the development of a gene therapy for CF. Drugs to treat the basic defect in CF represent a remarkable advance but cannot treat a significant cohort of patients with rare mutations. Thus, there is a critical need to develop a gene therapy for those individuals.     

Factors associated with self-rated health in primary care

Background: Self-rated health (SRH) measures one’s current general health and is a widely used health indicator. Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships are suspected to influence SRH, but studies in primary health care settings are sparse.

Objective: To examine the associations between patients’ self-rated health and their sleep problems, somatic health complaints, and unmet needs in interpersonal relationships.

Design: We collected data via questionnaires for this cross-sectional study from general practice.

Setting: Primary health care in Norway.

Subjects: 1302 consecutive patients participated.

Main outcome measures: The questionnaire included a single question about SRH, the Bergen Insomnia Scale (BIS), five questions on somatic health complaints, and three questions from the Basic Psychological Needs Scale (BPNS) pertaining to the relationships domain. We analyzed our data using ordinal logistic regression models.

Results: Our response rate was 74%. The prevalence of fair/poor SRH was 26%, with no gender differences. We revealed a significant association between increasing age and reduced SRH. The study showed that sleep problems and somatic health complaints were strongly associated with SRH, and unmet needs in relationships were also significantly and independently associated with reduced SRH in a full model analysis.

Conclusion: Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH. These factors are all modifiable and could be managed both within and outside a primary care setting in order to improve SRH.

• Key Points

• There was a high prevalence of reduced SRH in clinical general practice

• Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH

• These predictors are all modifiable with a potential to improve SRH

     

A qualitative study of clinical reasoning in physiotherapy with preterm infants and their parents: Action and interaction

Background: Physiotherapists (PTs) in primary health care provide services to preterm infants and their parents after hospital discharge. The service should be collaborative and individualized to meet the family’s needs. In this study, we analyze pediatric PTs’ collaborative work in the clinical setting and investigate the PTs’ emerging clinical reasoning (CR) in interaction with the infant and parent(s).

Methods: The study is based on observations of 20 physical therapy sessions and 20 interviews with PTs. We performed a systematic content analysis informed by enactive theory regarding the interactions and co-creation of meaning.

Results and Discussion: CR emerged in reciprocity with the PTs’ interaction with the infant and parent(s). Based on the sensitivity to the infant’s motor abilities and signs of engagement as well as the parents’ need of support and education, the PTs individualized and reasoned about their therapeutic approach. This interactional CR was vulnerable: infant disengagement, parent expectations, and PT preoccupations could obfuscate interactions and hamper CR.

Conclusion: Through mutuality and engagement with the infant and parent(s), the PTs allow the autonomy of interaction to emerge and shape the translation of CR into successful therapeutic actions and learning together with the infant and parent(s).     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

A 12-week interdisciplinary rehabilitation trial in patients with gliomas – a feasibility study

Purpose: This report aims to assess the safety and feasibility of using an interdisciplinary rehabilitation intervention for a future randomized controlled trial in patients with gliomas in the initial treatment phase.

Method: We conducted an outpatient two-part rehabilitation intervention that involved six weeks of therapeutic supervised training (part one) and six weeks of unsupervised training in a local gym following a training protocol (part two).

Results: Predefined feasibility objectives of safety (100%), consent rate (>80%), drop-out (<20%), adherence (>80%) and patient satisfaction (>80%) was achieved at part one. However, the failure to meet predefined feasibility objectives of drop-out, adherence and patient satisfaction of the unsupervised intervention at part two have led to a protocol revision for a future randomized controlled trial.

Conclusion: This study demonstrates that an intensive rehabilitation intervention of physical therapy and occupational therapy in the initial treatment phase of patients with gliomas whose Karnofsky performance status is ≥70 is safe and feasible, if relevant inclusion criteria and precautionary screening are made. With the revised protocol, we are confident that the foundation for conducting a successful randomized controlled trial among these vulnerable patients has been established.

• Implications for rehabilitation

• Brain tumors constitute some of the most challenging cancer diagnoses presenting for rehabilitation intervention.

• Patients with gliomas experiences limitations in physical functioning, cognition, and emotional wellbeing.

• In a relatively small sample this study shows that supervised physical- and occupational therapy in patients with gliomas is safe and feasible in the initial treatment phase.

• Patients with gliomas can potentially improve functioning through interdisciplinary rehabilitation

     

Consideration of treatment fidelity to improve manual therapy research

Objectives: The purpose of this paper was to define treatment fidelity, review its use in health care research and suggest how it may be utilized in manual therapy research to improve the reliability and validity of the literature.

Results: We offer an outline and a table of how manual therapy research may benefit from the concept of treatment fidelity.

Discussion: While treatment fidelity is a newer concept, and has not been integrated into Physical Therapy or Manual Therapy research, when utilized, it can have positive effects on the reliability and validity of the techniques we evaluate.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.