Treatment-focused Ebola trials,supportive care and future of filovirus care

Introduction: During the 2014–2016 Ebolavirus (EBOV) outbreak, several candidate therapeutics were used in EBOV-infected patients in clinical trials and under expanded access for emergency use. This review will focus briefly on medications used during the outbreak. We will discuss current therapeutic candidates and their status and will then turn to a related and essential topic: supportive care and the standard of care for filovirus infected patients. Potential benefits and pitfalls of combination therapies for filoviruses will be discussed.

Areas covered: Clinical trials of therapeutics targeting EBOV; clinical usage of therapeutics during recent EBOV outbreak; potential need for combination therapy; role of supportive care in treatment of Ebola virus disease (EVD).

Expert commentary: In the absence of another large scale EBOV outbreak, the path to therapeutic product licensure in the United States of America (USA) would need to be via the FDA Animal Rule. However, human data may be needed to supplement animal data. The future of filovirus therapeutics may therefore benefit by establishing the ability to implement clinical trials in an outbreak setting in a timely fashion. Supportive care guidelines for filovirus infection should be defined and established as standard of care for treatment of EVD.     

Advances in stem cell therapy for amyotrophic lateral sclerosis

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies.

Areas covered: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies.

Expert opinion: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.     

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.     

Serum osmolal gap in clinical practice: usefulness and limitations

Background: Although serum osmolal gap can be a useful diagnostic tool, clinicians are not familiar with its use in clinical practice.

Objectives: The review presents in a series of questions-answers and under a clinical point of view the current data regarding the use of osmolal gap.

Discussion: The definition and the best formula used for the calculation of osmolal gap, the main causes of increased osmolal gap with or without increased anion gap metabolic acidosis, as well as the role of concurrent lactic acidosis or ketoacidosis are presented under a clinical point of view.

Conclusions: The calculation of osmolal gap is crucial in the differential diagnosis of many patients presenting in emergency departments with possible drug or substance overdose as well as in comatose hospitalized patients.     

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.     

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

     

Effects of numerical information on intention to participate in cervical screening among women offered HPV vaccination: a randomised study

Objectives: To investigate the effects of different types of information about benefits and harms of cervical screening on intention to participate in screening among women in the first cohorts offered human papilloma virus (HPV) vaccination.

Design: Randomised survey study.

Setting: Denmark.

Subjects: A random sample of women from the birth cohorts 1993, 1994 and 1995 drawn from the general population.

Interventions: A web-based questionnaire and information intervention. We randomised potential respondents to one of the following four different information modules about benefits and harms of cervical screening: no information; non-numerical information; and two numerical information modules. Moreover, we provided HPV-vaccinated women in one of the arms with numerical information about benefits and harms in two steps: firstly, information without consideration of HPV vaccination and subsequently information conditional on HPV vaccination.

Main outcome measure: Self-reported intention to participate in cervical screening.

Results: A significantly lower proportion intended to participate in screening in the two groups of women receiving numerical information compared to controls with absolute differences of 10.5 (95% CI: 3.3–17.6) and 7.7 (95% CI: 0.4–14.9) percentage points, respectively. Among HPV-vaccinated women, we found a significantly lower intention to participate in screening after numerical information specific to vaccinated women (OR of 0.38).

Conclusions: Women are sensitive to numerical information about the benefits and harms of cervical screening. Specifically, our results suggest that HPV-vaccinated women are sensitive to information about the expected changes in benefits and harms of cervical screening after implementation of HPV vaccination.

• KEY POINTS

• Women were less likely to participate in cervical screening when they received numerical information about benefits and harms compared to non-numerical or no information.

• Specifically, numerical information about the potential impact of the reduced risk of cervical cancer among HPV-vaccinated women reduced the intention to participate among vaccinated women.

     

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.     

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.     

Working towards dengue as a vaccine-preventable disease: challenges and opportunities

Introduction: Dengue is an emerging viral disease that affects the human population around the globe. Recent advancements in dengue virus research have opened new avenues for the development of vaccines against dengue. The development of a vaccine against dengue is a challenging task because any of the four serotypes of dengue viruses can cause disease. The development of a dengue vaccine aims to provide balanced protection against all the serotypes. Several dengue vaccine candidates are in the developmental stages such as inactivated, live attenuated, recombinant subunit, and plasmid DNA vaccines.

Area covered: The authors provide an overview of the progress made in the development of much needed dengue vaccines. The authors include their expert opinion and their perspectives for future developments.

Expert opinion: Human trials of a live attenuated tetravalent chimeric vaccine have clearly demonstrated its potential as a dengue vaccine. Other vaccine candidate molecules such as DENVax, a recombinant chimeric vaccine andTetraVax, are at different stages of development at this time. The authors believe that the novel strategies for testing and improving the immune response of vaccine candidates in humans will eventually lead to the development of a successful dengue vaccine in future.     

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.     

The toxicity of picaridin containing insect repellent reported to the National Poison Data System

Context: While low toxicity is reported, there are sparse data on the safety of acute picaridin (icaridin) exposures in humans.

Objective: The purpose of this study was to review National Poison Data System (NPDS) data regarding ingestion of insect repellents containing picaridin and compare those to insect repellents containing DEET and other insect repellents not containing DEET.

Methods: NPDS was queried for single agent human insect repellent ingestions reported between 1 January 2000 and 31 May 2015 using the American Association of Poison Control Center generic categories 201048 (Insect Repellents with DEET) and 201049 (Insect Repellents without DEET). Picaridin-containing product exposures were assessed using Poisindex^® product ID 6744589. Insect repellents of unknown type were not included.

Results: 68,429 exposures occurred; 24% were non-DEET-containing products, of which 2% were picaridin-containing products. Among picaridin exposures, 92.9% were managed outside of a health-care facility; there were no reported cases of major effect or death, and only one case of moderate effect. Primary symptoms across all insect repellent exposures included ocular irritation/pain, vomiting, red eye/conjunctivitis, and oral irritation. Treatment primarily included dilution/irrigation/wash.

Conclusion: Unintentional ingestion of picaridin-containing and other insect repellents was associated only with minor toxicity and was generally managed outside of a health-care facility.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

General practitioners’ views on leadership roles and challenges in primary health care: a qualitative study

Objective: To explore general practitioners’ (GPs) views on leadership roles and leadership challenges in general practice and primary health care.

Design: We conducted focus groups (FGs) with 17 GPs.

Setting: Norwegian primary health care.

Subjects: 17 GPs who attended a 5 d course on leadership in primary health care.

Results: Our study suggests that the GPs experience a need for more preparation and formal training for the leadership role, and that they experienced tensions between the clinical and leadership role. GPs recognized the need to take on leadership roles in primary care, but their lack of leadership training and credentials, and the way in which their practices were organized and financed were barriers towards their involvement.

Conclusions: GPs experience tensions between the clinical and leadership role and note a lack of leadership training and awareness. There is a need for a more structured educational and career path for GPs, in which doctors are offered training and preparation in advance.

• KEY POINTS

• Little is known about doctors’ experiences and views about leadership in general practice and primary health care. Our study suggests that:

• There is a lack of preparation and formal training for the leadership role.

• GPs experience tensions between the clinical and leadership role.

• GPs recognize leadership challenges at a system level and that doctors should take on leadership roles in primary health care.

     

Optimizing the host substrate environment for cardiac angiogenesis,arteriogenesis, and myogenesis

Introduction: The diseased host milieu, such as endothelial dysfunction (ED), decreased NO bioavailability, and ischemic/inflammatory post-MI environment, hamper the clinical success of existing cardiac regenerative therapies.

Area covered: In this article, current strategies including pharmacological and nonpharmacological approaches for improving the diseased host milieu are reviewed. Specifically, the authors provide focus on: i) the mechanism of ED in patients with cardiovascular diseases, ii) the current results of ED improving strategies in pre-clinical and clinical studies, and iii) the use of biomaterials as a novel modulator in damaged post-MI environment.

Expert opinion: Adjunct therapies which improve host endothelial function have demonstrated promising outcomes, potentially overcoming disappointing results of cell therapy in human studies. In the future, elucidation of the interactions between the host tissue and therapeutic agents, as well as downstream signaling pathways, will be the next challenges in enhancing regenerative therapy. More careful investigations are also required to establish these agents’ safety and efficacy for wide usage in humans.     

Association between continuity of care in Swedish primary care and emergency services utilisation: a population-based cross-sectional study

Objective: The primary objective of this study was to determine the association between longitudinal continuity of care (CoC) in Swedish primary care (PC) and emergency services (ES) utilisation.

Study design: A cross-sectional analysis of longitudinal population data. Setting. PC centres, out-of-hours PC facilities and emergency departments (EDs) in Blekinge County in southern Sweden. Subjects: People of all ages who lived in Blekinge County and who had made two or more visits per year to a general practitioner (GP) during office hours from 1 January 2012 to 31 December 2014.

Main outcome measure: ES utilisation.

Results: Eight-thousand one-hundred and eighty-five people were included in the study. CoC was quantified using three different indices—Usual Provider of Care index (UPC), Continuity of Care index (CoCI), and Sequential Continuity index (SECON). The CoC that the PC centres could offer their enrolled patients varied significantly between the different centres, ranging from 0.23–0.57 for UPC, 0.12–0.43 for CoCI, and 0.25–0.52 for SECON. Association between the three CoC indices and ES utilisation was computed as an incidence rate ratio which ranged between 0.50 and 0.59.

Conclusion: Longitudinal CoC was shown to have a negative association with ES utilisation. The association was significant and of a magnitude that implies clinical relevance. Computed incidence rate ratios suggest that patients with the lowest CoC had twice as many ES visits compared to patients with the highest CoC.     

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.     

Adductor-related groin pain in the athlete

Background:

Owing to a multifactorial etiology, the differential diagnosis of groin pain in the athlete is often complex, with a diagnosis being clinically elusive in up to 30% of individuals. It has been suggested in the literature that the adductor musculature is a viable and prevalent source of groin pain. Thus, recognition of the elements related to effective management of these individuals is essential for the clinician.

Objectives:

To review the current literature related to prevalence, risk factors, clinical testing, conservative, and surgical interventions for adductor-related groin pain.

Major findings:

Adductor-related groin injuries may occur in isolation or combination. Athletes participating in multi-directional sports, with prior groin injury, weakness of adductors compared to abductors, and higher level of play are at greatest risk. Clinical testing using the adductor squeeze test at varying angles offers high specificity in the absence of imaging modalities. Evidence for preventative programs exists among soccer and ice hockey players. Interventions focusing on progressively improving adductor muscle performance and lower extremity impairments have been found effective, as have multi-modal interventions. Surgical interventions, recommended for those recalcitrant (>2 months) to conservative care appear effective, with adductor repair or tenotomy procedures being primarily described in case series designs.

Conclusion:

A paucity of research exists to determine the diagnostic utility of clinical tests as well as the efficacy of interventions. Clinicians should be aware of adductor-related groin pain as a clinical entity and recognize the potential merits and limitations of both preventive and adductor-focused interventions.     

What happens when the doctor denies a patient’s request? A qualitative interview study among general practitioners in Norway

Objective: To explore general practitioners (GPs’) experiences from consultations when a patient’s request is denied, and outcomes of such incidents.

Design and participants: We conducted a qualitative study with semi-structured individual interviews with six GPs in Norway. We asked them to tell about experiences from specific encounters where they had refused a patient’s request. The texts were analysed with Systematic Text Condensation, a method for thematic cross-case analysis.

Main outcome measures: Accounts of experiences from consultations when GPs refused their patients’ requests.

Results: Subjects of dispute included clinical topics like investigation and treatment, certification regarding welfare benefits and medico-legal issues, and administrative matters. The arguments took different paths, sometimes settled by reaching common ground but more often as unresolved disagreement with anger or irritation from the patient, sometimes with open hostility and violence. The aftermath and outcomes of these disputes lead to strong emotional impact where the doctors reflected upon the incidents and sometimes regretted their handling of the consultation. Some long-standing and close patient–doctor relationships were injured or came to an end.

Conclusions: The price for denying a patient’s request may be high, and GPs find themselves uncomfortable in such encounters. Skills pertaining to this particular challenge could be improved though education and training, drawing attention to negotiation of potential conflicts. Also, the notion that doctors have a professional commitment to his or her own autonomy and to society should be restored, through increased emphasis on core professional ethics in medical education at all levels.