Evaluation of the right ventricle by echocardiography: particularities and major challenges

Introduction: Compared with the left ventricle (LV), the right ventricle (RV) is less suited for evaluation by echocardiography (ECHO). Nevertheless, RV ECHO-assessment has currently emerged as an important diagnostic tool with meaningful prognostic value and essential contribution to therapeutic decisions. Although significant progress has been made, including generation of higher-quality normative data, validation of several two-dimensional measurements and improvements in three-dimensional ECHO-techniques, many challenges in RV ECHO-assessment still persist.

Areas covered: This review discusses the particular challenges and limits in obtaining accurate measurements of RV anatomical and functional parameters and focuses primarily on the difficulties in proper interpretation of the highly load dependent RV ECHO-parameters which complicates the use of this valuable diagnostic and surveillance technique.

Expert commentary: There is increasing evidence that RV assessment in relation with its actual loading conditions by ECHO-derived composite variables, which either incorporate a certain functional parameter and load, or incorporate measures which reflect the relationship between RV dilation and RV load, considering also the right atrial pressure (i.e. ‘load adaptation index’), is particularly suited for clinical decision-making. Load dependency of RV ECHO-parameters must be taken into consideration especially in patients with advanced RV dysfunction scheduled for LV assist device implantation or lung transplantation.     

Corneal epithelial stem cells for corneal injury

Introduction: Ocular surface diseases with limbal insufficiency represent a therapeutic challenge for restoring vision. This corneal deficiency includes both classical ocular diseases (as chemical burns) and rare ocular diseases (as congenital aniridia and ocular cicatricial pemphigoid).

Areas covered: Our understanding of limbal epithelial stem cells (LESCs) has increased the potential for treatment options. Pharmacological treatment strategies (as regenerating agent ophthalmic solutions) and especially surgical treatment strategies are available. Isolated LESCs can be produced by limbal primary cultures obtained from explants or cell suspensions. We review the latest cornea surgery techniques.

Expert opinion: The adjunction of human limbal mesenchymal cells as a support for limbal stem cell primary cultures appears to be of great interest. Recently, human-induced pluripotent stem cells have allowed the generation of minicorneal organoids. This potential means of creating a three-dimensional cornea with in vitro maturation opens up important research areas for corneal regeneration therapy.     

How to take arms against central apneas in heart failure

Introduction Despite being a risk mediator in several observational studies, central apneas are currently orphan of treatment in heart failure. After the neutral effects on survival of two randomized controlled trials (RCTs) based on the use of positive airway pressure (the CANPAP and SERVE-HF trials), two alternative hypotheses have been formulated:

1) Periodic breathing/Cheyne-Stokes respiration (PB/CSR) in HF is protective. Indeed, the Naughton’s hypothesis assumes that hyperventilation leads to increased cardiac output, lung volume, oxygen storage and reduced muscle sympathetic nerve activity, while central apnea to respiratory muscle rest and hypoxia-induced erythropoiesis.

2) The use of positive airway pressure is just a wrong treatment for PB/CSR. If this is the case, the search for novel potential alternative treatment approaches is mandatory in HF.

Areas covered This review will focus on the crucial issue of whether PB/CSR should be treated or not in HF, first by outlining the ideal design of pathophysiological studies to test the Naughton’s hypothesis and second by summarizing the treatment strategies so far proposed for PB/CSR in HF and identifying the most promising options to be tested in future RCTs.

Expert commentary It is likely that PB/CSR may be compensatory in some cases, but after a certain threshold (to be defined) it becomes maladaptive with negative prognostic meaning in HF. The development of a pathophysiologically based treatment targeting feedback resetting and neurohormonal activation underlying PB/CSR is likely to be the best option to obtain survival benefits in HF.     

Combining cell and gene therapy to advance cardiac regeneration

Introduction: The characterization of multipotent endogenous cardiac stem cells (eCSCs) and the breakthroughs of somatic cell reprogramming to boost cardiomyocyte replacement have fostered the prospect of achieving functional heart repair/regeneration.

Areas covered: Allogeneic CSC therapy through its paracrine stimulation of the endogenous resident reparative/regenerative process produces functional meaningful myocardial regeneration in pre-clinical porcine myocardial infarction models and is currently tested in the first-in-man human trial. The in vivo test of somatic reprogramming and cardioregenerative non-coding RNAs revived the interest in gene therapy for myocardial regeneration. The latter, together with the advent of genome editing, has prompted most recent efforts to produce genetically-modified allogeneic CSCs that secrete cardioregenerative factors to optimize effective myocardial repair.

Expert opinion: The current war against heart failure epidemics in western countries seeks to find effective treatments to set back the failing hearts prolonging human lifespan. Off-the-shelf allogeneic-genetically-modified CSCs producing regenerative agents are a novel and evolving therapy set to be affordable, safe, effective and available at all times for myocardial regeneration to either prevent or treat heart failure.     

Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer

Introduction: Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease.

Areas Covered: This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease.

A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy.

Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.     

Biological therapy for non-obstructive azoospermia

Introduction: Most male patients with non-obstructive azoospermia (NOA) have no therapeutic options outside of assisted reproductive techniques to conceive a biological child. If mature sperm cannot be obtained from the testes, these patients must rely on options of donor sperm or adoption. Several techniques are in the experimental stage to provide this patient population alternatives for conceiving.

Areas covered: This review discusses three of the experimental techniques for restoring fertility in men with NOA: spermatogonial stem cell transplantation, the use of adult and embryonic stem cells to develop mature gametes and gene therapy. After this discussion, the authors give their expert opinion and provide the reader with their perspectives for the future.

Expert opinion: Several limitations, both technical and ethical, exist for spermatogonial stem cell transplantation, the use of stem cells and gene therapy. Well-defined reproducible protocols are necessary. Furthermore, several technical barriers exist for all protocols. And while success has been achieved in animal models, future research is still required in human models.     

Treating childhood traumatic brain injury with autologous stem cell therapy

Introduction: Neonatal traumatic brain injury (TBI) is a significant cause of developmental disorders. Autologous stem cell therapy may enhance neonatal brain plasticity towards repair of the injured neonatal brain.

Areas covered: The endogenous neonatal anti-inflammatory response can be enhanced through the delivery of anti-inflammatory agents. Stem cell therapy stands as a robust approach for sequestering the inflammation-induced cell death in the injured brain. Here, we discuss the use of umbilical cord blood cells and bone marrow stromal cells for acute and chronic treatment of experimental neonatal TBI. Autologous stem cell transplantation may dampen neuroinflammation. Clinical translation of this stem cell therapy will require identifying the therapeutic window post-injury and harvesting ample supply of transplantable autologous stem cells. Stem cell banking of cryopreserved cells may allow readily available transplantable cells and circumvent the unpredictable nature of neonatal TBI. Harnessing the anti-inflammatory properties of stem cells is key in combating the progressive neurodegeneration after the initial injury.

Expert opinion: Combination treatments, such as with hypothermia, may enhance the therapeutic effects of stem cells. Stem cell therapy has immense potential as a stand-alone or adjunctive therapy for treating neuroinflammation associated with neonatal TBI acutely and for preventing further progression of the injury.     

Myocardial healing using cardiac fat

Introduction: Chronic diseases, including myocardial scar healing and heart failure remission, impose huge social and economic burdens, and novel approaches are needed. Several therapeutic modalities are currently being evaluated, including cell therapy, stem cell conditioning, and cardiac tissue engineering.

Areas covered: This review discusses the restoration of cardiac function after myocardial infarction using a vascularized flap of autologous cardiac adipose tissue over an akinetic scar. It addresses the risks and benefits of using cardiac adipose progenitors and the adipose graft transposition procedure (AGTP) to ameliorate cardiac dysfunction in preclinical and clinical trials.

Expert commentary: The focus is shifting from first-generation studies that used ex vivo expanded and manipulated progenitors to newer second-generation approaches, including AGTP, which are inexpensive and do not raise ethical issues. AGTP safety has been validated, and the ongoing AGTP-2 trial to determine AGTP efficacy and outcome is currently recruiting patients (NCT02798276). This reparative strategy is safe, avoids the risks associated with ex vivo manipulation, and the preclinical and clinical trials performed to date show cardiac function recovery and reduced necrosis. Confirmation of these data in the AGTP-2 trial could pave the way for the clinical use of this novel modality.     

The use of soft robotics in cardiovascular therapy

Introduction: Robots have been employed in cardiovascular therapy as surgical tools and for automation of hospital systems. Soft robots are a new kind of robot made of soft deformable materials, that are uniquely suited for biomedical applications because they are inherently less likely to injure body tissues and more likely to adapt to biological environments. Awareness of the soft robotic systems under development will help promote clinician involvement in their successful clinical translation.

Areas covered: The most advanced soft robotic systems, across the size scale from nano to macro, that have shown the most promise for clinical application in cardiovascular therapy because they offer solutions where a clear therapeutic need still exists. We discuss nano and micro scale technology that could help improve targeted therapy for cardiac regeneration in ischemic heart disease, and soft robots for mechanical circulatory support. Additionally, we suggest where the gaps in the technology currently lie.

Expert commentary: Soft robotic technology has now matured from the proof-of-concept phase to successful animal testing. With further refinement in materials and clinician guided application, they will be a useful complement for cardiovascular therapy.     

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.     

Eat,breathe, ROS: controlling stem cell fate through metabolism

Introduction: Research reveals cardiac regeneration exists at levels previously deemed unattainable. Clinical trials using stem cells demonstrate promising cardiomyogenic and regenerative potential but insufficient contractile recovery. Incomplete understanding of the biology of administered cells likely contributes to inconsistent patient outcomes. Metabolism is a core component of many well-characterized stem cell types, and metabolic changes fundamentally alter stem cell fate from self-renewal to lineage commitment, and vice versa. However, the metabolism of stem cells currently studied for cardiac regeneration remains incompletely understood.

Areas covered: Key metabolic features of stem cells are reviewed and unique stem cell metabolic characteristics are discussed. Metabolic changes altering stem cell fate are considered from quiescence and self-renewal to lineage commitment. Key metabolic concepts are applied toward examining cardiac regeneration through stem cell-based approaches, and clinical implications of current cell therapies are evaluated to identify potential areas of improvement.

Expert commentary: The metabolism and biology of stem cells used for cardiac therapy remain poorly characterized. A growing appreciation for the fundamental relationship between stem cell functionality and metabolic phenotype is developing. Future studies unraveling links between cardiac stem cell metabolism and regenerative potential may considerably improve treatment strategies and therapeutic outcomes.     

Myocardial infarction with non obstructive coronary arteries (MINOCA): a whole new ball game

Introduction: MINOCA is a clinical syndrome that encompasses a subgroup of heterogeneous patients who present with myocardial infarction yet do not have any significant coronary artery obstruction on angiogram. As many as one in ten patients with acute myocardial infarction (AMI) will not have an occluded coronary artery, and the reported prevalence keeps rising, in part due to better recognition of this syndrome. Current guidelines offer several diagnostic algorithms but MINOCA remains largely under-recognised and little is known about whether patients might benefit from a more specific treatment modality.

Areas covered: We review pathogenesis, diagnosis, prognosis, and management of MINOCA.

Expert commentary: Due to the significant heterogeneity of MINOCA patients, a more efficient management strategy may solely rely on an individualized approach in order to improve outcomes.     

Use of panel testing for detection of antinuclear antibody in a resource-limited setting: an appraisal

Objectives: Despite an increase in the incidence of systemic connective tissue diseases (CTD), panel testing for detection of antinuclear antibodies (ANA) is not a routine practice in many health centers of the Indian subcontinent. Consequently, the data on its significance is scanty.

Methods: To evaluate utility of panel testing, line immunoassay (LIA) and indirect immunofluorescence antinuclear antibody test (IIF-ANA) were performed in 321 cases of CTD.

Results: Out of 321 serum samples screened by the above tests, 227 were positive and 18 were negative by both LIA and IIF-ANA. Additional 11/321 (3.4%) cases were picked up by LIA. SSA was most common specificity in these cases followed by SSA/SSB, SSB, Ro-52, Jo-1, dsDNA and nRNP/Sm.

Conclusion: Use of LIA along with IF-ANA and ELISA improves sensitivity of CTD screening.     

Danish general practitioners’ self-reported competences in end-of-life care

Objective: General practitioners (GPs) are pivotal in end-of-life (EOL) care. This study aimed to assess GP-reported provision of EOL care and to assess associations with GP characteristics.

Design: Population-based questionnaire study.

Setting: Central Denmark Region with approximately 1.3 million inhabitants.

Subjects: All 843 active GPs in the Central Denmark Region were sent a questionnaire by mail.

Main outcome measures: Responses to 18 items concerning four aspects: provision of EOL care to patients with different diagnosis, confidence with being a key worker, organisation of EOL care and EOL skills (medical and psychosocial).

Results: In total, 573 (68%) GPs responded. Of these, 85% often/always offered EOL care to cancer patients, which was twice as often as to patients with non-malignancies (34–40%). Moreover, 76% felt confident about being a key worker, 60% had a proactive approach, and 58% talked to their patients about dying. Only 9% kept a register of patients with EOL needs, and 19% had specific EOL procedures. GP confidence with own EOL skills varied; from 55% feeling confident using terminal medications to 90% feeling confident treating nausea/vomiting. Increasing GP age was associated with increased confidence about being a key worker and provision of EOL care to patients with non-malignancies. In rural areas, GPs were more confident about administering medicine subcutaneously than in urban areas.

Conclusion: We found considerable diversity in self-reported EOL care competences. Interventions should focus on increasing GPs’ provision of EOL care to patients with non-malignancies, promoting better EOL care concerning organisation and symptom management.

• KEY POINTS

• GPs are pivotal in end-of-life (EOL) care, but their involvement has been questioned. Hence, GPs’ perceived competencies were explored.

• GPs were twice as likely to provide EOL care for patients with cancer than for patients with non-malignancies.

• EOL care was lacking clear organisation in general practice in terms of registering palliative patients and having specific EOL procedures.

• GPs were generally least confident with their skills in terminal medical treatment, for example, using medicine administered subcutaneously.

     

Social disparities in diabetes care: a general population study in Denmark

Objective: We investigated the association between socioeconomic factors and the attainment of treatment goals and pharmacotherapy in patients with type 2 diabetes in Denmark.

Design: A cross-sectional population study.

Setting: The municipality of Naestved, Denmark.

Subjects: We studied 907 patients with type 2 diabetes identified from a random sample of 21,205 Danish citizens.

Main outcome measures: The proportion of patients who were not achieving goals for diabetes care based on their HbA_1c, LDL-cholesterol, blood pressure, and lifestyle, and the proportion of patients who were treated with antihypertensive and cholesterol- and glucose-lowering medication.

Methods: We investigated the association of the socioeconomic factors such as age, gender, education, occupation, income, and civil status and attainment of treatment goals and pharmacotherapy in logistic regression analyses. We investigated effect modification of cardiovascular disease and kidney disease.

Results: Middle age (40–65 years), low education level (i.e. basic schooling), and low household income (i.e. less than 21,400 € per year) were associated with nonattainment of goals for diabetes care. The association of socioeconomic factors with attainment of individual treatment goals varied. Patients with low socioeconomic status were more often obese, physically inactive, smoking, and had elevated blood pressure. Socioeconomic factors were not associated with treatment goals for hyperglycemia. Socioeconomic factors were inconsistently associated with pharmacotherapy. There was no difference in contacts to general practitioners according to SES.

Conclusions: In a country with free access to health care, the socioeconomic factors such as middle age, low education, and low income were associated with nonattainment of goals for diabetes care.

• KEY POINTS

• Middle age, low education, and low income were associated with nonattainment of goals for diabetes care, especially for lifestyle goals.

• Patients with low socioeconomic status were more often obese, physically inactive, smoking, and had elevated blood pressure.

• Association of socioeconomic factors with pharmacotherapy was inconsistent.

     

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.     

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

     

Using biomarkers to guide heart failure management

Introduction: Biomarkers have revolutionized the diagnosis of heart failure (HF), but it remains unclear how to use biomarkers to guide management of HF.

Areas covered: An exhaustive literature search on using biomarkers to guide HF management was performed. HF guidelines were carefully scrutinized for references pertaining to this topic, and Medline was employed to identify further references. This review focused on natriuretic peptides, troponin, and ST2 as biomarkers used to guide HF management. Most trials have examined secondary prevention of chronic HF patients, and data on primary prevention of HF and therapy of acute HF are emerging.

Expert commentary: While the current data on using biomarkers to guide HF management remain mixed, more research is necessary to better understand how to utilize biomarkers to improve HF management.     

Induced neural stem cells as a means of treatment in Huntington’s disease

Introduction: Huntington’s disease (HD) is an inherited neurodegenerative disease characterized by chorea, dementia, and depression caused by progressive nerve cell degeneration, which is triggered by expanded CAG repeats in the huntingtin (Htt) gene. Currently, there is no cure for this disease, nor is there an effective medicine available to delay or improve the physical, mental, and behavioral severities caused by it.

Areas covered: In this review, the authors describe the use of induced neural stem cells (iNSCs) by direct conversion technology, which offers great advantages as a therapeutic cell type to treat HD.

Expert opinion: Cell conversion of somatic cells into a desired stem cell type is one of the most promising treatments for HD because it could be facilitated for the generation of patient-specific neural stem cells. The induced pluripotent stem cells (iPSCs) have a powerful potential for differentiation into neurons, but they may cause teratoma formation due to an undifferentiated pluripotent stem cell after transplantation Therefore, direct conversion of somatic cells into iNSCs is a promising alternative technology in regenerative medicine and the iNSCs may be provided as a therapeutic cell source for Huntington’s disease.     

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.