Sherwood Forest Hospitals NHS Foundation Trust

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The discovery of malignant cells in pleural fluid and/or parietal pleura signifies disseminated or advanced disease and a reduced life expectancy in patients with cancer.1 Median survival following diagnosis ranges from 3 to 12 months and is dependent on the stage and type of the underlying malignancy. The shortest survival time is observed in malignant effusions secondary to lung cancer and the longest in ovarian cancer, while malignant effusions due to an unknown primary have an intermediate survival time.2–6 Historically, studies showed that median survival times in effusions due to carcinoma of the breast are 5–6 months. However, more recent studies have suggested longer survival times of up to 15 months.7–10 A comparison of survival times in breast cancer effusions in published studies to 1994 calculated a median survival of 11 months.9 Currently, lung cancer is the most common metastatic tumour to the pleura in men and breast cancer in women.4 11 Together, both malignancies account for 50–65% of all malignant effusions (table 1). Lymphomas, tumours of the genitourinary tract and gastrointestinal tract account for a further 25%.2 12–14 Pleural effusions from an unknown primary are responsible for 7–15% of all malignant pleural effusions.3 13 14 Few studies have estimated the proportion of pleural effusions due to mesothelioma: studies from 1975, 1985 and 1987 identified mesothelioma in 1/271, 3/472 and 22/592 patients, respectively, but there are no more recent data to update this in light of the increasing incidence of mesothelioma.4 13 14 View this table: Table 1 Primary tumour site in patients with malignant pleural effusion Attempts have been made to predict survival based on the clinical characteristics of pleural fluid. None has shown a definite correlation: a recent systematic review of studies including 433 patients assessing the predictive value of pH concluded that low pH does not reliably predict …

Abstract Rationale Single-center randomized controlled trials of the Zephyr endobronchial valve (EBV) treatment have demonstrated benefit in severe heterogeneous emphysema. This is the first multicenter study evaluating this treatment approach. Objectives To evaluate the efficacy and safety of Zephyr EBVs in patients with heterogeneous emphysema and absence of collateral ventilation. Methods This was a prospective, multicenter 2:1 randomized controlled trial of EBVs plus standard of care or standard of care alone (SoC). Primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute-walk distance, St. George’s Respiratory Questionnaire score, and modified Medical Research Council score were assessed at 3 and 6 months, and target lobe volume reduction on chest computed tomography at 3 months. Measurements and Main Results Ninety seven subjects were randomized to EBV (n = 65) or SoC (n = 32). At 3 months, 55.4% of EBV and 6.5% of SoC subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: EBV 56.3% versus SoC 3.2% (P < 0.001), with a mean ± SD change in FEV1 at 6 months of 20.7 ± 29.6% and −8.6 ± 13.0%, respectively. A total of 89.8% of EBV subjects had target lobe volume reduction greater than or equal to 350 ml, mean 1.09 ± 0.62 L (P < 0.001). Between-group differences for changes at 6 months were statistically and clinically significant: ΔEBV–SoC for residual volume, −700 ml; 6-minute-walk distance, +78.7 m; St. George’s Respiratory Questionnaire score, −6.5 points; modified Medical Research Council dyspnea score, −0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, −1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of EBV subjects. Conclusions EBV treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance, and quality of life, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT02022683).

AIMS: To determine whether patients with diabetes without prior myocardial infarction (MI) have the same risk of total coronary heart disease (CHD) events as non-diabetic patients with previous myocardial infarction. METHODS: Using MEDLINE, EMBASE, Cochrane and MeSH in this systematic review and meta-analysis, extensive searching was carried out by cross-referencing from original articles and reviews. The study consisted of cohort or observational studies with hard clinical endpoints, including total CHD events (fatal or non-fatal myocardial infarction), stratified for patients with diabetes but no previous myocardial infarction, and patients without diabetes but with previous myocardial infarction. Studies with less than 100 subjects, follow-up of less than 4 years and/or without provisions for calculating CHD event rates were excluded. The review of articles and data extraction was performed by two independent authors, with any disagreements resolved by consensus. RESULTS: Thirteen studies were included involving 45,108 patients. The duration of follow-up was 5-25 years (mean 13.4 years) and the age range was 25-84 years. Patients with diabetes without prior myocardial infarction have a 43% lower risk of developing total CHD events compared with patients without diabetes with previous myocardial infarction (summary odds ratio 0.56, 95% confidence interval 0.53-0.60). CONCLUSION: This meta-analysis did not support the hypothesis that diabetes is a 'coronary heart disease equivalent'. Public health decisions to initiate cardio-protective drugs in patients with diabetes for primary CHD prevention should therefore be based on appropriate patients' CHD risk estimates rather than a 'blanket' approach of treatment.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

### Spontaneous pneumothorax #### Acute management for spontaneous pneumothorax ##### Recommendations ##### Good practice points #### Optimal management after the resolution of a first episode of pneumothorax ##### Good practice points #### Optimal management for spontaneous pneumothorax and ongoing air leak ##### Good practice point

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Obstructive sleep apnoea (OSA) is a cardio-metabolic disorder. Whether metabolic syndrome (MS), insulin resistance (IR) and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV) risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP) were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA) value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF) criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence) and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p < 0.001). The prevalence of microalbuminuria in both groups was negligible. Logistic regression adjusted for age, BMI and smoking showed that the patient with OSA was 5.9 (95% CI 2.0-17.6) times more likely to have MS than non-OSA patient. Triglyceride (p = 0.031), glucose (0.023) and Epworth score (0.003) values were independently associated with OSA after adjusting for BMI and other covariates whilst IR status was found not to be significant. Using the ROC curve analysis, we found that a waist circumference of >103 cm would predict MS in patients with OSA at 75-78% sensitivity and 61-64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.

BACKGROUND: His-bundle pacing (HBP) provides physiological ventricular activation. Observational studies have demonstrated the techniques' feasibility; however, data have come from a limited number of centers. OBJECTIVES: We set out to explore the contemporary global practice in HBP focusing on the learning curve, procedural characteristics, and outcomes. METHODS: This is a retrospective, multicenter observational study of patients undergoing attempted HBP at seven centers. Pacing indication, fluoroscopy time, HBP thresholds, and lead reintervention and deactivation rates were recorded. Where centers had systematically recorded implant success rates from the outset, these were collated. RESULTS: A total of 529 patients underwent attempted HBP during the study period (2014-19) with a mean follow-up of 217 ± 303 days. Most implants were for bradycardia indications. In the three centers with the systematic collation of all attempts, the overall implant success rate was 81%, which improved to 87% after completion of 40 cases. All seven centers reported data on successful implants. The mean fluoroscopy time was 11.7 ± 12.0 minutes, the His-bundle capture threshold at implant was 1.4 ± 0.9 V at 0.8 ± 0.3 ms, and it was 1.3 ± 1.2 V at 0.9 ± 0.2 ms at last device check. HBP lead reintervention or deactivation (for lead displacement or rise in threshold) occurred in 7.5% of successful implants. There was evidence of a learning curve: fluoroscopy time and HBP capture threshold reduced with greater experience, plateauing after approximately 30-50 cases. CONCLUSION: We found that it is feasible to establish a successful HBP program, using the currently available implantation tools. For physicians who are experienced at pacemaker implantation, the steepest part of the learning curve appears to be over the first 30-50 cases.

The sodium-glucose co-transporter-2 (SGLT2) is a low-affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. The observation that individuals with familial renal glycosuria maintain normal long-term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Intense research in this therapeutic area has led to the discovery of novel SGLT2 inhibitors, each with different chemical, pharmacodynamic and pharmacokinetic profiles. This review outlines the biology, expression and pleotropic activity of the SGLT system and the pharmacological profile of SGLT2 inhibitors and provides a summary of preclinical and limited clinical data available to characterize the efficacy, safety and potential clinical utility of SGLT2 inhibitors in the management of diabetes.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration: ISRCTN Identifier: ISRCTN47845793.

OBJECTIVES: The aim of this study was to assess the evidence and available literature on the clinical, pathogenetic, prognostic and therapeutic aspects of Computer vision syndrome. METHODS: Information was collected from Medline, Embase & National Library of Medicine over the last 30 years up to March 2016. The bibliographies of relevant articles were searched for additional references. FINDINGS: Patients with Computer vision syndrome present to a variety of different specialists, including General Practitioners, Neurologists, Stroke physicians and Ophthalmologists. While the condition is common, there is a poor awareness in the public and among health professionals. INTERPRETATIONS AND IMPLICATIONS: Recognising this condition in the clinic or in emergency situations like the TIA clinic is crucial. The implications are potentially huge in view of the extensive and widespread use of computers and visual display units. Greater public awareness of Computer vision syndrome and education of health professionals is vital. Preventive strategies should form part of work place ergonomics routinely. Prompt and correct recognition is important to allow management and avoid unnecessary treatments.

OBJECTIVE: Structural changes of osteoarthritis (OA) may occur in the absence of pain. In this study, we aimed to identify histopathologic features that are associated with symptomatic knee OA. METHODS: Medial tibial plateaus and synovium samples were obtained at the time of total knee replacement (TKR) surgery for OA (advanced OA group) or were obtained postmortem from subjects who had not sought medical attention for knee pain during the last year of life (non-OA control group). To identify features of OA, we compared the patients with advanced OA with the age-matched non-OA controls (n = 26 per group). To identify OA features associated with symptoms, we compared two additional groups of subjects who were matched for severity of chondropathy (n = 29 per group): patients undergoing TKR for symptomatic OA (symptomatic chondropathy group) and postmortem subjects with similar severity of chondropathy who were asymptomatic during the last year of life (asymptomatic chondropathy group). The histologic features of the samples were graded, and immunoreactivities for macrophages (CD68) and nerve growth factor (NGF) in the synovium were quantified. The cellular localization of synovial NGF was determined by double immunofluorescence analysis. RESULTS: Advanced OA cases displayed more severe changes in the synovium (synovitis, increased synovial NGF, and CD68-immunoreactive macrophages) and cartilage (loss of cartilage surface integrity, loss of proteoglycan, tidemark breaching, and alterations in chondrocyte morphology) than did the non-OA controls. Synovial NGF was localized predominantly to fibroblasts and to some macrophages. The symptomatic chondropathy group displayed greater levels of synovitis, synovial NGF, and loss of cartilage integrity, in addition to alterations in chondrocyte morphology, than did the asymptomatic chondropathy group (P < 0.05 for each comparison). CONCLUSION: Synovitis, increased synovial NGF, alterations in chondrocyte morphology, and loss of cartilage integrity are features of knee OA that may be associated with symptoms.

The aim of this article was to describe (i) the epidemiology and outcomes of stroke relating to diabetes; (ii) the pathophysiology of diabetes as a risk factor for stroke; (iii) the management of acute stroke in patients with diabetes; (iv) the evidence of primary and secondary prevention of stroke in patients with diabetes; and (v) the risk of new-onset diabetes using older antihypertensive agents. The combination of diabetes and stroke disease is a major cause of morbidity and mortality worldwide. Evidence from large clinical trials performed in patients with diabetes supports the need for aggressive and early intervention to target patients' cardiovascular (CV) risks in order to prevent the onset, recurrence and progression of acute stroke. Identification of at-risk patients with diabetes and metabolic syndrome has also allowed the delivery of early and effective intervention to reduce stroke risks, while active treatment during the acute phase of stroke will reduce long-term neurological and functional deficits. While the ongoing debate on the risk benefits of different antihypertensive, lipid-lowering and antiplatelet agents should not detract clinicians from pursuing aggressive CV risk reduction, the application of evidence-based medicine specifically in patients with diabetes will facilitate the use of appropriate agents to improve clinical outcomes. The overall management of patients with diabetes and acute stroke or at risk of secondary stroke should also include multifactorial intervention that not only targets patient's CV risk but also includes behavioural, lifestyle and, where appropriate, surgical intervention.

INTRODUCTION: Pain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA. METHODS: In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status. RESULTS: More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health. CONCLUSIONS: Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.

OBJECTIVE: To assess the feasibility of conducting a randomised controlled trial of a home-based virtual reality system for rehabilitation of the arm following stroke. DESIGN: Two group feasibility randomised controlled trial of intervention versus usual care. SETTING: Patients' homes. PARTICIPANTS: Patients aged 18 or over, with residual arm dysfunction following stroke and no longer receiving any other intensive rehabilitation. INTERVENTIONS: Eight weeks' use of a low cost home-based virtual reality system employing infra-red capture to translate the position of the hand into game play or usual care. MAIN MEASURES: The primary objective was to collect information on the feasibility of a trial, including recruitment, collection of outcome measures and staff support required. Patients were assessed at three time points using the Wolf Motor Function Test, Nine-Hole Peg Test, Motor Activity Log and Nottingham Extended Activities of Daily Living. RESULTS: Over 15 months only 47 people were referred to the team. Twenty seven were randomised and 18 (67%) of those completed final outcome measures. Sample size calculation based on data from the Wolf Motor Function Test indicated a requirement for 38 per group. There was a significantly greater change from baseline in the intervention group on midpoint Wolf Grip strength and two subscales of the final Motor Activity Log. Training in the use of the equipment took a median of 230 minutes per patient. CONCLUSIONS: To achieve the required sample size, a definitive home-based trial would require additional strategies to boost recruitment rates and adequate resources for patient support.

Understanding of the causes and underlying mechanisms of pain in people with RA is rapidly changing. With the advent of more effective disease modifying drugs, joint inflammation is becoming a more treatable cause of pain, and joint damage can often be prevented. However, the long-term prognosis for pain still is often unfavourable, even after inflammation is suppressed. Pain is associated with fatigue and psychological distress, and RA pain qualities often share characteristics with neuropathic pain. Each of these characteristics suggests key roles for central neuronal processing in RA pain. Pain processing by the central nervous system can maintain and augment RA pain, and is a promising target for future treatments. Inflammatory mediators, such as cytokines, may provoke central pain sensitisation in animal models, and both local and systemic inflammation might contribute to central pain augmentation in RA. Controlled trials of treatments that target central pain processing have shown some benefit in people with RA, and might be most effective in individuals for whom central pain augmentation plays a key role. For people with RA who experience persistent pain, identifying underlying pain mechanisms critically determines the balance between escalation of anti-inflammatory and disease-modifying treatments and other strategies to provide symptomatic analgesia.

The endemic area for dengue fever extends over 60 countries, and approximately 2.5 billion people are at risk of infection. The incidence of dengue has multiplied many times over the last five decades at an alarming rate. In the endemic areas, waves of infection occur in epidemics, with thousands of individuals affected, creating a huge burden on the limited resources of a country's health care system. While the illness passes off as a simple febrile episode in many, a few have a severe illness marked by hypovolemic shock and bleeding. Iatrogenic fluid overload in the management may further complicate the picture. In this severe form dengue can be fatal. Tackling the burden of dengue is impeded by several issues, including a lack of understanding about the exact pathophysiology of the infection, inability to successfully control the vector population, lack of specific therapy against the virus, and the technical difficulties in developing a vaccine. This review provides an overview on the epidemiology, natural history, management strategies, and future directions for research on dengue, including the potential for development of a vaccine.

Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A(1c) (HbA(1c)) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA(1c) reduction with DPP-IV inhibitors depends upon the pretreatment HbA(1c) values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.

BACKGROUND AND PURPOSE: There is inconclusive evidence of the effectiveness of the Stroke Family Support Organiser (FSO) service. We report the results from a randomized controlled trial of the service. METHODS: Stroke patients admitted to hospital and their informal caregivers were randomly allocated to receive the FSO service (n=126) or standard care (n=124). Outcome assessments were undertaken 4 and 9 months after recruitment with the General Health Questionnaire 12, Carer Strain Index, Barthel Index, Extended Activities of Daily Living scale, and a specially designed questionnaire to determine knowledge of stroke and satisfaction with services. RESULTS: There were no significant differences between groups in patients' mood and independence in personal or instrumental activities of daily living or caregivers' mood, strain, or independence. Patients in the intervention group were significantly more knowledgeable about whom to contact for stroke information, reducing the risk of stroke, practical help, community services, and emotional support. Patients in the intervention group were also significantly more satisfied with the stroke information received. Caregivers in the intervention group were significantly more knowledgeable about whom to contact for information on stroke, reducing the risk of stroke, community services, and emotional support. Caregivers in the intervention group were also significantly more satisfied with stroke information. CONCLUSIONS: The FSO service had no significant effect on mood, independence in activities of daily living, or reduction in caregiver strain, but it did increase knowledge of stroke and satisfaction with that knowledge. The results may not be representative of all FSO services, and the sample was small relative to the heterogeneity of the participants. However, results suggest that the policies and training procedures of FSOs need to be evaluated to ensure that a cost-effective service is being provided to stroke patients and their caregivers.