This review identifies an agenda for global health by highlighting the current ‘grand challenges’ related to governance.
Literature from the disciplines of health policy and medicine, conference presentations and documents, and materials from international agencies (such as the World Health Organization).
The present approach to global health governance has proven to be inadequate and major changes are necessary.
The source of problems behind the current global health governance challenges have not always been agreed upon, but this paper attempts to highlight the recurrent themes and topics of consensus that have emerged in recent years.
A solution to the ‘grand challenges’ in global health governance is urgently needed and serves as an area for developing research.
Cellular reprogramming is the process of directing mature cells to a primitive state of gene expression.
Medline searches using the keywords ‘pluripotency’, ‘induce’ (and derivatives), and/or ‘stem’ limited to the years 2006 to the present and other selected literature known to the author.
Since 2006, there has been a cavalcade of scientific works describing so-called ‘direct reprogramming’ wherein somatic cells are forced into a state of gene expression very similar to embryonic stem cells. These findings build upon prior research using nuclear transfer (cloning) and even older efforts to understand developmental processes.
While already of tremendous research value, it remains to be seen how (if) direct reprogramming methodologies will be refined for clinical use.
A greater understanding of epigenetics, the process by which different patterns of gene expression are established, maintained and redirected, will continue to be enlightened by advances in cellular reprogramming.
Rotaviruses (RVs) are an important cause of acute gastroenteritis in infants and young children worldwide, resulting in more than 600 000 deaths per annum, mainly in developing countries. Since the 1980s, there has been intensive research on the development of RV vaccine candidates, and since 2006 two vaccines have been licensed in many countries.
The scientific literature since the 1970s has been consulted, and the results of original research carried out in authors' laboratories were used.
There are firmly established data on virus particle structure, genome composition, gene–protein assignment, protein-function assignment (incomplete), virus classification, the mechanisms of several steps of the replication cycle (adsorption, primary transcription, virus maturation—all partial), several mechanisms of pathogenesis, aspects of the immune response, diagnosis, illness and treatment, epidemiology and vaccine development.
Research on the following areas is still in full flux and in part not generally accepted: several steps of the replication cycle (mechanism of viral entry into host cells, mechanisms of packaging and reassortment of viral RNAs, morphogenesis of subviral particles in viroplasms and maturation of virus particles in the rough endoplasmic reticulum (RER) with temporary acquisition and subsequent loss of an envelope), the true correlates of protection and the long-term effectiveness of RV vaccines.
Recently, a system that allows carrying out reverse genetics with some of the RV genes has been established which, however, has limitations. There is intensive research ongoing, which is trying to develop better and universally applicable reverse genetics systems. There is broad research on the molecular mechanisms of the immune response and on which immunological parameter correlates best with lasting protection from severe RV disease. Research into other than live attenuated vaccines is growing.
The establishment of better reverse genetics systems for RVs is the most important research goal for both the understanding of the molecular biology of RVs and the development of new and safe RV vaccines. The black boxes of our knowledge on aspects of RV replication (RNA packaging, RNA replication, control of reassortment and functions of the non-structural RV proteins) are under intensive research.
This article considers the process of re-classification of prescription drugs from prescription-only medications to over-the-counter (OTC) prescription drugs.
The recent change in classification for emergency contraception and simvastatin is explored in detail with similarities and differences being considered for a similar argument to be made for sildenafil.
The benefits for patients, physicians and other healthcare professionals are considered in detail.
We raise concerns about recently developed and existing patient group directions that, although extensive in their assessment, may omit to identify significant contributory factors which would necessitate appropriate medical intervention.
While the decision for re-classification to OTC would depend on a number of factors, we argue that, with the proviso of proper assessments being made, sildenafil should be made available as an OTC medication.
The safety and use of OTC medications for erectile dysfunction at a time when many first line prescription agents are reaching generic status.
Increasing numbers of medicines are being made available over the counter in the UK, by purchase in a pharmacy or from other less well-regulated outlets. When this is allowed by the Licensing Authority, it is often subject to certain restrictions. However, some drugs that could usefully be converted from prescription-only medicines (PoM status) to over-the-counter sales in a pharmacy (P status) are not suitable for full over-the-counter status, even with restrictions; and in some cases restrictions vitiate the usefulness of the medicine.
Drugs that can acceptably be switched from PoM status to P status include those that are used in the treatment of minor ailments or injuries, for health promotion or in palliative care.
However, not all drugs that are being switched fall into these categories. Ready availability of antimicrobial drugs over the counter, one of which (azithromycin) has recently been switched, could encourage the emergence of resistant organisms. Drugs that are used for long-term treatment and lifestyle drugs are also controversial, particularly if their adverse effects are of potential concern. On the other hand, the availability of many drugs via the internet removes the ability of regulators to control the supply of such drugs.
A new category of purchase, Pharmacist Consultation and Supply, with built-in safeguards, could improve the availability of some medicines under more careful control than is currently available for over-the-counter medicines.
Although several epidemiological studies demonstrate the association between resting heart rate (HR) and cardiovascular morbidity and mortality, an elevated HR remains a neglected cardiovascular risk factor.
This review summarizes the results of published studies on the relationship between elevated HR and cardiovascular risk.
The role of HR in myocardial ischaemia in coronary patients is well known. Experimental data and clinical observations support the importance of HR in the pathophysiology of atherosclerosis and plaque rupture. A large body of evidence points to high resting HR as a risk factor for mortality in various populations, including coronary patients.
HR reduction is suggested to be a mechanism explaining the prognostic benefit of beta-blockers after myocardial infarction or in heart failure patients. However, it was unclear whether HR reduction per se directly affects cardiovascular prognosis. Treatment with ivabradine, a pure HR-reducing agent, provides an opportunity to assess the effects of selectively lowering HR without altering other aspects of cardiac function.
The results of the recent Morbidity–Mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction study underline the importance of HR reduction in the management of stable coronary artery disease. The prospective analysis of data from the placebo arm demonstrated that elevated resting HR (≥70 bpm) is a strong independent predictor of clinical outcomes. Consistent with these data, ivabradine significantly improved coronary outcomes in patients with a HR of 70 bpm or more.
These data support the importance of HR in the management of stable coronary artery disease to assess prognosis and to guide optimal therapy.
Despite advances in knowledge and refinements of technique, the management of flexor tendon injuries within the digital sheath continues to present a formidable challenge. This in turn has led to a massive expansion in search of modified surgical therapies and various adjuvant therapies, which could prevent adhesion formation without compromising digital function.
A search of PubMed, Medline, CINAHL and Embase databases was performed using the keywords ‘tendon adhesion prevention’, ‘tendon healing’, ‘adhesion prevention in tendons’ and ‘adjuvants for adhesion prevention’. Studies detailing the use of surgical, pharmacological and non-pharmacological agents for adhesion prevention in digital flexor tendons were identified, and their bibliographies were thoroughly reviewed to identify further related articles. This search identified 41 studies, which investigated the use of various pharmacological agents in adhesion prevention in digital tendons.
There is a need to develop and utilize an optimal method for the prevention of adhesions in the flexor tendons of the hand, due to post-surgical complications.
Even though there have been significant advances in the prevention of adhesions in flexor tendons, it remains to be proved which, if any, of the current methods are the most beneficial.
The only thing that appears clinically justified in adhesion prevention is the need for early post-operative mobilization of digits after tendon injury or repair but the best method of mobilization remains controversial.
Suggested changes in surgical techniques and various proposed pharmacological and non-pharmacological modalities need to withstand the test of adequately powered human trials, before their justification for potential benefit in clinical practice is accepted.
Heavy exercise induces marked immunodepression, which is multifactorial in origin. Evidence showing clinical significance of this immunodepression is scarce.
We assessed in a systematic manner whether physical activity or intensity of exercise increase susceptibility to upper respiratory tract infections (URTI). A literature search was performed using the keywords ‘upper respiratory tract infections’, ‘athletes’, ‘exercise’ and ‘physical activity’. We considered all studies reporting of the effect of exercise, physical activity, sport and training on susceptibility to URTI. A total of 162 publications were identified and 30 studies were eligible (4 descriptive, 18 observational and 8 interventional). The 30 studies included 8595 athletes (5471 runners, 2803 swimmers) and 1798 non-athletes.
Moderate activity may enhance immune function, whereas prolonged, high-intensity exercise temporarily impairs the immune competence. Athletes, when compared with lesser active individuals, experience higher rate of URTI after training and competitions. In non-athletes, increasing physical activity is associated with a decreased risk of URTI.
The relationship between exercise and URTI is affected by poorly known individual determinants such as genetic factors, fitness, nutritional status or atopy. Elite athletes may have a decreased susceptibility to URTI.
The dose–response relationship between immunodepression and risk for URTI during the weeks following heavy exercise. What are the clinically relevant methods to assess exercise-induced immunodepression? Is down-regulation of immunity after intense exercise a protective response to limit inflammation? Is there a role for nutritional or pharmaceutical interventions to reduce risk of URTI?
The management of unstable slipped upper femoral epiphysis (SUFE) is controversial, with a high risk of developing avascular necrosis (AVN). We meta-analysed two areas of concern: reduction of the slip and the timing of treatment.
A search of Medline, CINAHL and Embase identified only retrospectively relevant studies: four regarding the role of reduction and five regarding the timing of treatment. The incidence of AVN was compared between reduced and unreduced SUFEs, and between those treated within 24 h of symptom onset and those treated thereafter.
Analysis of the pooled data gave an odds ratio of 2.20 (P = 0.290) in favour of the unreduced group, who had a lower risk of developing AVN. The odds ratio was 0.50 in favour of the group treated within 24 h from symptom onset (P = 0.441). However, though clinically important, these effects were not statistically significant.
The timing of treatment is somewhat inconsistent: two studies favour management more than 24 h after the onset of symptoms, while for three unstable SUFEs are best managed within 24 h.
Despite the non-significant results from the meta-analysis, it can be suggested that, if reduction is to be performed, it should be undertaken cautiously, as it may be associated with increased AVN. The ideal time for management of unstable slip is probably within 24 h of symptom onset.
There is a strong need for multicentre, randomized, controlled trials in this area.
The advent of AIDS brought about a group of patients unwilling to accept crucial aspects of the methodological standards for clinical research investigating Phase 1 drugs, surgeries or devices. Their arguments against placebo controls in trials, which depended—at the time—on the terminal status of patient volunteers led to a renewed discussion of the ethics of denying patients with catastrophic illnesses access to last-chance experimental drugs, surgeries or devices.
Existing ethics and health policy literature on the topic of access to experimental drugs.
The positions of those arguing for or against free access to experimental drugs for terminally ill patients are irreconcilable.
At stake are questions about the kinds of personal sacrifices society can reasonably expect patients in clinical trials to make to ensure statistically predictive results. These would benefit by necessity a much larger number of current and future patients—the conflict is about individual versus public interests. It is also about the question of whether or not the state can legitimately prevent patients with terminal illnesses from unfettered access to experimental drugs, surgeries or devices in order to motivate them to participate in clinical trials. We review the ethical arguments for and against the provision of access to Phase 1 agents for terminally ill patients.
Finding a compromise between providing free or no access to Phase 1 drugs for terminally ill patients.
We ought to investigate means to increase access to experimental drugs for terminally ill patients without sacrificing necessary clinical trials' sounds scientific methods.
Since many anti-cancer agents act by inflicting DNA damage on tumour cells, there is increasing interest in the use of inhibitors of DNA repair to increase the cytotoxicity of these agents. Poly(ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme that binds to sites of DNA damage and promotes repair by modifying a number of key proteins. Potent and specific inhibitors of PARP are available; these have been shown to increase the cytotoxicity of a range of anti-cancer agents including temozolomide, irinotecan and radiation.
Data from laboratory studies on human tumour cell lines, pre-clinical studies including tumour xenograft models and early phase clinical testing in human subjects are discussed.
Pre-clinical and early clinical testing indicates that PARP inhibitors are extremely well tolerated. As single agents they have activity against BRCA1- and BRCA2-deficient cancers, and in combination they increase the cytotoxic effects of certain chemotherapy agents.
In order for PARP inhibitors to improve outcomes for patients, their sensitizing effects must be tumour specific. Early clinical data indicate that systemic toxicity may be exacerbated, so future trials must address this issue. The mechanism of action of PARP inhibitors in combination with cytotoxic agents is also uncertain.
Among BRCA-deficient cancers, mechanisms of inherent and acquired resistance to PARP inhibitors are under investigation. Combining these agents with radiotherapy appears promising but designing clinical trials to test the efficacy and toxicity of this combination is problematic.
A particularly promising role for PARP inhibitors in the treatment of malignant brain tumours is outlined.
We conducted a systematic review of the current literature for this review, but as there are many gaps in the research literature, we have supplemented this by our own clinical experience.
There is a general agreement that Asperger syndrome (AS) is one of the autistic spectrum disorders, that it is a developmental disorder which is either present at birth or develops shortly after and that there is a strong hereditary component.
The fundamental impairment of AS is in the social arena, but what causes this is disputed. We propose that it is a disorder of non-verbal communication. Another important area of controversy is the extent to which AS may remit.
Many people with AS develop secondary psychiatric disorders in adolescence and adulthood, some of which may be linked genetically, notably bipolar disorder [DeLong R, Nohria C (1994) Psychiatric family history and neurological disease in autistic spectrum disorders. Dev Med Child Neurol, 36, 441–448] or be explicable by some other association, but many patients and carers attribute their anxiety and low mood to bullying. The prevalence, treatment and prevention of co-morbid mental health problems are rapidly developing areas of interest. Some people with AS are known to commit offences, and when they commit they are more likely to be violent offences against strangers. How much of a risk that is presented by people with AS, and how to assess this risk, is another growing area of concern.
The social impairments of people with AS include deficits in empathy, self-awareness and executive function. Many of these are quintessentially human characteristics, and the study of people with AS provides opportunities for using neuroimaging to compare people with AS and controls and identify which areas of the brain are concerned with these ‘higher functions’. The study of AS, like that of other fronto-striatal disorders, is also throwing light on the role of networks in the brain and on how networks are formed during embryogenesis.
The increasing number of available cardiac imaging techniques has made the investigation of coronary artery disease (CAD) more complex. Appropriate patient referral depends on an understanding of the pre-test likelihood of CAD and the information provided by each test.
This article describes myocardial perfusion scintigraphy (MPS) and summarizes evidence for its role in stable CAD and acute coronary syndromes with particular reference to current guidelines.
MPS has been extensively validated for the cost-effective diagnosis and prognosis of functionally significant CAD in both the acute and chronic settings. Its use is emphasized in the current NICE, national and international guidelines.
Although normal MPS is associated with good outcomes, assessments of subclinical atherosclerosis such as coronary artery calcium scoring and computed tomography coronary angiography (CTA) demonstrate that non-flow-limiting CAD remains prognostically important.
Technological developments, such as attenuation correction to improve diagnostic accuracy or analysis of left ventricular phase to detect dyssynchrony, carry the possibility of increasing the information that can be usefully gained from a single MPS study.
Of particular importance will be the role of MPS in an integrated imaging strategy that involves both anatomical and functional cardiac assessments. The use of hybrid technology that combines techniques such as MPS and CTA into a single imaging unit requires careful consideration with regard to diagnostic usefulness and cost-effectiveness.
Cardiac arrest is a common emergency in acute hospitals. The Resuscitation Council (UK) Advanced Life Support Guidelines provide a systematic approach to cardiac arrest recognition, treatment and aftercare. This review provides an update on the current treatment guidelines and identifies areas where these may be strengthened.
The evidence informing the 2005 Resuscitation Guidelines is reviewed. New evidence since the publication of the guidelines was identified by searching Medline (December 2005–December 2008) with the term heart arrest or advanced life support.
Opportunities for strengthening the chain of survival exist for each link. These include better recognition of critically ill patients at risk of cardiac arrest, improved quality of cardiopulmonary resuscitation, defibrillation strategies, which minimize pre- and post-shock pauses and development of post-resuscitation care bundles.
Emerging evidence suggests opportunities where Resuscitation Guidelines could be strengthened by focusing on specific aspects of the chain of survival.
Infection is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Research on CF infection has highlighted differences from other respiratory infections—both in the range and the nature of the organisms—especially in chronic infection. This is a rapidly advancing field of microbiology and is bringing insights into the complexity and adaptations of bacteria causing chronic infection in the respiratory tract.
The epidemiology of some infections in CF has changed, with reduction in spread of Burkholderia cenocepacia following patient segregation. Conversely, epidemic strains of Pseudomonas aeruginosa have emerged, which spread between patients; previously, most P. aeruginosa strains were patient-specific. Studies on hypermutators, quorum sensing, biofilm growth and the development of molecular identification have shed light on pathogenicity, microbial adaptation to the host and complexity of infection in CF. Non-tuberculous mycobacteria are emerging pathogens in CF; however, there is much to learn about pathogenicity and treatment of these infections. Species of aerobic and anaerobic bacteria, more commonly encountered in the upper tract, are found in significant numbers in CF sputum. The significance of this is however under debate. Finally, although the clinical relevance of conventional antibiotic susceptibility testing for chronic CF pathogens has been questioned, there are no clear alternatives.
Much has been learnt about pathogenicity, evolution of CF pathogens and development of antibiotic resistance. The need is to focus on clinical relevance of these observations to improve diagnosis, prevention and treatment of CF infection.
The current study provides an overview of history and evolution in total ankle arthroplasty.
We conducted a comprehensive literature search without limitations to language. Information from any source, providing evidence of the use ankle of prostheses (e.g. biomechanical testing, cadaveric implantations or clinical use) was evaluated. Data regarding biomechanical concepts, design considerations, published results (patient numbers, surgical method, follow-up, complications and survival rates) were collected.
Only level IV studies were found. Mobile-bearing prostheses are mainly used in Europe, and fixed-bearing implants are mainly used in the USA. The current designs' failure rate is 10–12% at ~5 years. Survival rates vary among different institutions. Increased surgeons' experience is associated with better outcomes.
Biomechanical studies and review of previous implant failures has led to the development of a new generation of implants.
Results show that ankle arthroplasty is a viable alternative for the management of ankle arthritis in selected patients.
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. In industrialized countries, intravenous drug users (IDUs) are the main reservoir of infection. Relatively little information is available on HCV in the developing world.
Peer reviewed publications and presentations at major academic meetings.
HCV-related cirrhosis and death from hepatocellular carcinoma are likely to rise dramatically in the next three decades. Urgent intervention is required both to minimize the burden of disease in those already infected and to reduce the incidence of new infections, particularly in the IDU population.
Current models of care and commissioning in the UK and other countries do not adequately identify or treat HCV infection in IDUs. Most strategies focus on disease prevention and do not target new infections.
New models of care are currently being developed and validated.
The development of new models of HCV replication will transform our understanding and capacity to treat HCV infection.
Ultrasound is widely used for imaging purposes and as an adjunct to physiotherapy. Low-intensity pulsed ultrasound (LIPUS), having removed the thermal component found at higher intensities, is used to improve bone healing. However, its potential role in soft-tissue healing is still under investigation.
We searched on Medline using the keywords: low-intensity pulsed ultrasound, LIPUS and LIPUS and soft-tissue healing. Thirty-two suitable articles were identified.
Research, mainly pre-clinical, so far has shown encouraging result, with LIPUS able to promote healing in various soft tissues such as cartilage, inter-vertebral disc, etc. The effect on the bone-tendon junction, however, is primarily on bone. The role of LIPUS in treating tendinopathies is questionable. Adequately powered human studies with standardisation of intensities and dosages of LIPUS for each target tissue are needed.
Aicardi–Goutières syndrome (AGS) is an autosomal recessive encephalopathy characterized by acquired microcephaly, cerebral calcifications, leukodystrophy, cerebral atrophy and cerebrospinal fluid findings of chronic lymphocytosis and raised interferon-alpha (INF-alpha). The main extraneurological symptoms are chilblain-like skin lesions, usually on the fingers, toes and ears.
This review is based on a search of the published literature on AGS from 1984 onwards (particularly the most recent papers) and on knowledge and experience gained through the authors' work with the International Aicardi-Goutières Syndrome Association (IAGSA).
It is accepted that AGS can be mistaken for a congenital infection and that the diagnostic significance of its cardinal signs (raised INF-alpha levels, basal ganglia calcifications) is different in different stages of the disease. Currently, we know of four genes that, if mutated, can give rise to AGS, but at least one other gene is believed to exist. These genes are involved in the DNA damage response, a defect of which could provoke an inappropriate innate immune response, triggering increased secretion of INF-alpha, ultimately responsible for the main features of the disease.
The natural history of AGS has not yet been definitively described given the lack of extensive, long-term neuroradiological follow-up studies. Furthermore, it is not yet clearly understood how the innate immune system is activated, what triggers the onset of the disease or why it tends to ‘burn out’ after several months. Immunosuppressive therapy in the active stage of the disease does not seem to produce any real change in the clinical course, but more data are needed.
Current studies aim to clarify the molecular mechanisms underlying the pathogenesis of AGS and to establish the exact pathway by which retained nucleic acids activate the immune system. This knowledge could allow the development of therapeutic strategies.
Psychological reactions to terror attacks have been documented as ranging from no symptoms to transient behavioural symptoms to more serious posttraumatic stress.
A review of representative studies is presented, with a critical analysis of the salient points of the various psychological intervention strategies for terrorist attacks.
Common aspects of both most intervention approaches include multifaceted models that foster social support and include a preparatory phase, a phase of ‘psychological first aid’ and a follow-up phase of referral for more severe cases.
The notion of intervention for all who may show some symptoms is not universally accepted. Where treatment or intervention is used, the debriefing aspect of CISM (Critical Incident Stress Management) remains highly disputed, with the focus on intrusively revisiting the trauma appearing to have questionable value at best.
Some data questions whether formal treatment or intervention is necessary or even desirable. For many who choose not to seek out any help following a trauma, clinical data shows no negative results. Moreover, the preponderance of data shows that conventional ‘debriefing’ is not recommended. If the debriefing mechanism is refined so that intrusive emotional rehashing of the traumatic event is eliminated, the resultant interventions resemble resilience based approaches.
Further defining when intervention is called for and refining the mechanisms of intervention in multi-stage intervention.
The time around a patient's death is often filled with sadness, but good medical and nursing care can provide comfort to patients and their carers at this critical time. For many, a ‘pain-free’ death is a priority although there are other aspects to providing good care at the end of life. Honest, open discussion with patients and carers about their wishes is an essential prerequisite to individualized care.
Relevant literature was reviewed with regards to policy, education and delivery of end of life care.
Pain management must be tailored to the individual with due regard to the route of analgesic administration in those unable to swallow, and consideration to the other circumstances surrounding a person's care. All staff caring for dying patients should address pain as a priority in managing end of life care, to promote the best possible death for patients and prevent undue distress for carers and staff.
This review has approached patient care at the end of life within current UK legislation, outlining what can be done to promote a ‘pain-free’ death. Debate continues about the role of euthanasia within end of life care and the use of analgesics and sedatives in pain management in terminal care.
There is a range of tools available to help staff to care for dying patients, such as the Liverpool Care Pathway (LCP) for the Dying. It is most effective when introduced as part of a wider system of staff education in relation to terminal care.
Research into care of the dying will continue to be challenging. Priorities include; whether the use of tools such as the LCP improve the care patients receive, and the development of routine outcome measures including validated reports from patients and proxies.
People with schizophrenia have difficulties in interpreting social information. Much social information is gathered from faces, and face processing represents a well-characterized model to study the basis of social deficits in schizophrenia.
A narrative review of selected literature.
Individuals with schizophrenia have impairments in recognizing basic emotions and making social judgements from facial stimuli.
The neural basis of these abnormalities is still being determined. However, initial evidence implicates dysfunction of frontal and temporal lobe brain regions. Hyper-activation of the amygdala, a brain region involved in fear, to facial stimuli may be an important underlying neural abnormality.
The present article highlights the difficulties that people with schizophrenia have in interpreting social cues from faces.
Research is required to understand more about both the basis of social deficits in schizophrenia and their potential remediation.
The burden of human papillomavirus (HPV)-associated ano-genital disease is significant but the ability to generate HPV virus-like particles by the synthesis and self-assembly in vitro of the major virus coat protein L1 has transformed our prospects for preventing benign and malignant ano-genital disease caused by the common genital HPV types.
Peer reviewed journals.
Two HPV L1 vaccines have been developed, a quadrivalent HPV 6/11/16/18, and a bivalent HPV 16/18 product. Both vaccines are very immunogenic and well tolerated. They have been shown in the various randomized Control trials to be very effective at preventing infection and premalignant disease related to the vaccine HPV genotypes in women who were DNA negative and sero negative for the vaccine HPV types at base line. The protection against disease generated by the vaccines persists for at least 5 years. HPV vaccines containing HPV 6/11 will reduce the incidence of genital warts by 80–90% in the medium term. The vaccines will reduce but not eliminate the risk of cervical cancer since at the present they only target two of the oncogenic genital types. Cervical cancer screening programmes will remain as important secondary interventions for cervical cancer even in vaccinated populations.
The duration of protection remains unknown but there is evidence of good immune memory, it is possible that protection will be long lasting. The primary target group for cost effective immunization with HPV vaccines are peri-pubertal females. There may be benefit in vaccinating other groups (men, sexually active women of all ages) but the cost effectiveness of these interventions will need to be evaluated. In societies in which organized screening programmes are not available, HPV vaccines are probably the most realistic intervention against HPV-associated disease.
Second generation vaccines that offer protection against additional types, are thermostable and delivered by non-injection methods are an important area of investigation.
Atrial fibrillation (AF) is the most common, sustained rhythm disturbance. The prevalence of AF is increasing as people live longer. Common conditions such as hypertension and ischaemic heart disease play an important role in the development of AF. The presence of AF is associated with increased morbidity and mortality from stroke and heart failure, particularly in patients with structural heart disease.
This article provides evidence-based information on the key aspects of managing AF which is based on major guidelines, landmark clinical trials and meta-analyses.
It is well recognized that both rate control and rhythm control are important strategies for the management of AF, but each approach should be chosen according to individual patient circumstances. A vast majority of elderly, relatively asymptomatic patients will benefit from ventricular rate control. Embolic stroke remains a major complication of AF. Yet, anticoagulation with warfarin remains underprescribed, especially in the elderly due to the presumed risk of bleeding. The technique of catheter ablation continues to improve and is generally successful in younger patients with relatively normal hearts.
There are clinically relevant differences among published schemes designed to stratify stroke risk in patients with AF. The CHADS2 score is currently the most simple system to give some initial estimate of stroke risk in AF patients, but could significantly underestimate this risk, particularly in those who fall in the ‘intermediate’ risk category.
Novel antiarrhythmic agents, including atrial specific agents with improved efficacy and safety profile, are currently under development. New antithrombotic agents with efficacy similar to warfarin which do not require regular INR testing appear to be promising, but there are lack of data about their long-term safety. There is increasing evidence that inflammation and fibrosis may play a major role in the initiation and maintenance of AF. Statins by means of their pleotropic effects and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers by preventing atrial remodelling may prove useful in preventing the development of AF. However, there is insufficient evidence to expand the use of these agents to a wider patient population at risk of AF. It needs to be seen if strategies towards primary and secondary prevention with treatment of underlying heart disease and modification of risk factors have a larger effect than specific interventions in preventing the burden of AF in the general population.
Inflammatory bowel disease (IBD) results from complex interactions between: host genome, immune system, mucosa, bacteria, and environment.
Review of PubMed database using search terms ‘bacteria and inflammatory bowel disease’ and ‘genetics and inflammatory bowel disease’. PubMed ‘related reference’ feature and references from retrieved articles were examined.
IBD results from interaction between the microbiota of the gut and the immune system. Key gene defects associated with IBD are involved in bacterial recognition and processing. The environment at least modifies and may determine pathogenesis.
It has been disputed whether the primary defect in IBD is immunological or bacterial, and which bacteria are key.
‘M cells’, the specialized epithelial cells that overlie Peyer's patches, are a major interface between gut bacteria and the immune system. Improved understanding is needed of the bacteria involved in IBD pathogenesis, their genotypes and phenotypes, their portal of entry and their mechanism for escaping attack from the immune system. Bacterial ligands involved in bacteria–epithelial adhesion are emerging, and molecular techniques are rapidly increasing our knowledge of the human intestinal microbiota.
Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing β-cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials.
Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review.
Early genetic studies identified the most important region for genetic susceptibility to T1D—the human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility.
Historically, there have been many controversial genetic associations with T1D, mostly caused by underpowered case–control studies but these are now decreasing in frequency.
The functional effect of each gene associated with T1D must be investigated to determine its usefulness both in risk assessment and as a potential therapeutic target.
Recently identified copy number variants in DNA and epigenetic modifications (heritable changes not associated with changes in the DNA sequence) are also likely to play a role in genetic susceptibility to T1D.
The prevalence of type 2 diabetes and dementia are set to rise inexorably over the next 30–40 years. There are now substantial data to suggest that type 2 diabetes is associated with an increased risk of dementia.
This is a narrative review using data from individual studies and review articles known to the authors. A Medline search was also undertaken and reference lists were reviewed to identify additional relevant studies.
Type 2 diabetes is associated with an increased risk of both Alzheimer's and Vascular dementia, although the reality is that many affected individuals have mixed forms of dementia.
The mechanisms underpinning this association remain to be clearly delineated. Type 2 diabetes is a complex disorder and so it is likely that multiple different, synergistic processes may interact to promote cognitive decrements.
Recent data suggest that glucocorticoids excess and elevated inflammatory markers may also have a role in the aetiology of diabetes-related cognitive impairment.
Large-scale, prospective epidemiological studies are now required to accurately delineate the pathogenesis of cognitive impairment in people with type 2 diabetes. These are underway and randomized trials of diabetes-specific interventions are also starting to include cognitive function as an outcome measure.
Current methods of fracture care use various adjuncts to try and decrease time to fracture union, improve fracture union rates and enhance functional recovery. Intermittent pneumatic compression (IPC), one such modality, is used in the management of both fractures and soft-tissue injuries.
A search of PubMed, Medline, CINAHL, DH data and Embase databases was performed using the following keywords ‘intermittent pneumatic compression’, ‘fracture healing’ and ‘soft tissue healing’. Sixteen studies on the use of IPC in fracture and soft-tissue healing were identified. These studies demonstrated that IPC facilitates both fracture and soft-tissue healing with rapid functional recovery.
IPC appears to be an effective modality to enhance fracture and soft-tissue healing. However, the number of subjects in human studies is small, and adequately powered randomized controlled trials in humans are required to produce stronger clinically relevant evidence.
Coeliac disease is a common but often under diagnosed condition with important complications. It is due to immune-mediated gluten intolerance and may present in a number of ways. It has become more frequently diagnosed due to the recognition of the atypical presentations. In recent years, more sensitive and specific serological markers have been developed but the gold standard of diagnosis remains duodenal biopsy. Compliance with a strict, lifelong gluten-free diet is the cornerstone of management, improving symptoms and reducing complications of the disease.
For this review, we focused on papers published on coeliac disease in recent years. Particular emphasis was given to clinical papers examining new methods for the diagnosis of coeliac disease or newer therapies for managing complications. The main source was PubMed and the major gastroenterology journals.
Coeliac disease is more common than once thought with a prevalence of around 1%. Diagnosis should always be confirmed with a duodenal biopsy. Management of coeliac disease with a gluten-free diet remains the cornerstone of treatment.
Some complications of coeliac disease, especially neurological, are not widely accepted despite growing support from the literature. Management of enteropathy-associated lymphoma has been difficult, and the optimal therapy is not known.
Current understanding is such that coeliac disease is the most widely understood autoimmune condition. ‘Atypical’ presentations are becoming the most common presenting features of coeliac disease.
Alternatives to the gluten-free diet are about to go into clinical studies. Similarly, better serological screening tests may obviate the need for duodenal biopsy.
This review will try to summarize the current understanding of coeliac disease with regard to diagnosis, management, complications and future perspectives.
The results of operative management of tennis elbow are varied, and the indications for surgery are not well codified. Many operative techniques are reported, but a clear consensus on whether a given surgical procedure is more effective over another is yet to be reached.
We conducted a MEDLINE, CINAHL and EMBASE search on all available scientific articles that reported the outcomes of surgery for lateral epicondylopathy. Keywords used were ‘tennis elbow’, ‘lateral epicondylitis’, ‘lateral epicondylalgia’, ‘tendinopathy’, ‘tendonitis’ and ‘tendon’. Subheadings used were ‘surgery’, ‘outcomes’, ‘pathology’, ‘physiology’ and ‘operation’. All relevant articles were retrieved. Each article was scored using the Coleman methodology score (CMS), a highly repeatable methodology score, by two independent reviewers, followed by data analysis.
The mean CMS for the 45 studies identified was 43 ± 9 (of a possible 100 points), with ‘number of patients’, ‘type of study’, ‘outcome criteria and assessment’ and ‘subject selection process’ being the major low scorers. Also, there was no improvement in the CMS, and hence study design, over the years (intra-class correlation coefficient = 0.45).
There is a dearth of quality evidence available to be able to advocate one operative technique over another.
We stress the need for well-designed adequately powered randomized controlled trials to be able to understand which of these operative techniques is really superior to the others.