Frequency and nature of potentially harmful preventable problems in primary care from the patient's perspective with clinician review: a population-level survey in Great Britain.

OBJECTIVES: To estimate the frequency of patient-perceived potentially harmful problems occurring in primary care. To describe the type of problem, patient predictors of perceiving a problem, the primary care service involved, how the problem was discussed and patient suggestions as to how the problem might have been prevented. To describe clinician/public opinions regarding the likelihood that the patient-described scenario is potentially harmful. DESIGN: Population-level survey. SETTING: Great Britain. PARTICIPANTS: A nationally representative sample of 3975 members of the public aged ≥15 years interviewed during April 2016. MAIN OUTCOME MEASURES: Counts of patient-perceived potentially harmful problems in the last 12 months, descriptions of patient-described scenarios and review by clinicians/members of the public. RESULTS: 3975 of 3996 participants in a nationally representative survey completed the relevant questions (99.5%). 300 (7.6%; 95% CI 6.7% to 8.4%) of respondents reported experiencing a potentially harmful preventable problem in primary care during the past 12 months and 145 (48%) discussed their concerns within primary care. This did not vary with age, gender or type of service used. A substantial minority (30%) of the patient-perceived problems occurred outside general practice, particularly the dental surgery, walk in clinic, out of hours care and pharmacy. Patients perceiving a potentially harmful preventable problem were eight times more likely to have 'no confidence and trust in primary care' compared with 'yes, definitely' (OR 7.9; 95% CI 5.9 to 10.7) but those who discussed their perceived-problem appeared to maintain higher trust and confidence. Generally, clinicians ranked the patient-described scenarios as unlikely to be potentially harmful. CONCLUSIONS: This study highlights the importance of actively soliciting patient's views about preventable harm in primary care as patients frequently perceive potentially harmful preventable problems and make useful suggestions for their prevention. Such engagement may also help to improve confidence and trust in primary care.

Development and piloting of a survey to estimate the frequency and nature of potentially harmful preventable problems in primary care from a UK patient's perspective.

OBJECTIVES: To design and pilot a survey to be used at the population level to estimate the frequency of patient-perceived potentially harmful preventable problems occurring in UK primary care. To explore the nature of the problems, patient-suggested strategies for prevention and opinions of clinicians and the public regarding the potential for harm. DESIGN: A survey was codesigned by three members of the public and one researcher and piloted through public and patient involvement and engagement networks. SETTING: Self-selected sample of the UK population. PARTICIPANTS: 977 members of the public accessed the online survey during October and November 2015. PRIMARY OUTCOME MEASURES: Respondent feedback about the ease of completion of the survey, quality of responses in terms of review by clinicians and members of the public, preliminary estimates of the frequency and nature of patient-perceived potentially harmful problems occurring in the last 12 months. RESULTS: 638 (65%) members of the public completed the survey and few respondents reported any difficulty in understanding or completing the survey. 132 (21%) respondents reported experiencing a potentially harmful preventable problem during the past 12 months and 108 (82%) of these respondents provided a description that was adequate for at least one clinician to form an opinion about the potentially harmful problem. Respondents were older than the UK generally, more likely to work or volunteer in the healthcare sector and tended to use primary care more frequently but their confidence and trust in their own general practitioner (GP) was similar to that of the UK population as measured by the annual English GP patient survey. CONCLUSIONS: The survey was acceptable to patients and mostly provided data of sufficient quality for review by clinicians and members of the public. It is now ready to use at a population level to estimate the frequency and nature of potentially harmful preventable problems in primary care from a patient's perspective.

Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

Insulin-stimulated mitochondrial adenosine triphosphate synthesis is blunted in skeletal muscles of high-fat-fed rats.

Physiologic elevation of insulin levels induces a significant increase in muscle adenosine triphosphate (ATP) synthesis rate in normal individuals, indicative of an appropriate acceleration in mitochondrial activity. However, the stimulatory effect of insulin is diminished in insulin-resistant patients. In the absence of similar data from preclinical models, the present study investigated the inhibitory effects of increased dietary fat intake on insulin-stimulated ATP synthesis rates in rats. After being placed on a high-fat diet for 8 weeks (n = 10), diet-induced obese male Sprague-Dawley rats were tested against age-matched control rats (n = 9) on a normal chow diet. Muscle ATP synthase flux rates were measured under anesthesia by in vivo (31)P saturation transfer both before and during a euglycemic-hyperinsulinemic clamp. The glucose infusion rates observed during the clamp revealed impaired peripheral insulin sensitivity in the high-fat-fed rats when compared with the age-matched control rats. Under baseline conditions (ie, low insulin), the muscle ATP synthesis rates of high-fat-fed rats were approximately 30% lower (P < .05) than those in chow-fed rats. Moreover, chow-fed animals showed a significant increase (25%, P < .05 vs basal) in muscle ATP synthesis activity upon insulin stimulation, whereas high-fat-fed animals displayed no substantial change. These data demonstrated for the first time in a preclinical model that the insulin challenge not only facilitates an improvement in the dynamic range of ATP turnover measurement by (31)P saturation transfer between normal and insulin-resistant rats, but also mimics challenge that is relevant for pharmacologic studies on antidiabetic drugs aimed at improving mitochondrial function.

Diet-induced modulation of mitochondrial activity in rat muscle.

Growing evidence supports the theory that mitochondrial dysfunction is an underlying cause of intramyocellular lipid (IMCL) accumulation and insulin resistance. Here, we hypothesized that high dietary fat (HF) intake could trigger changes in mitochondrial activity such that fatty acid oxidation is impaired in muscle and contributes to an elevation in intramyocellular lipid (IMCL) levels. Muscle mitochondrial activity was determined in vivo through measurement of the F(1)F(0) ATP synthase flux, the terminal step in the oxidative phosphorylation process. An initial study comparing rats on normal chow diet with rats on an HF diet revealed strong correlations between muscle ATP synthesis rates, IMCL levels and whole body glucose tolerance. Results obtained from two latter studies showed multiphasic responses to dietary intervention. Initially, the ATP synthesis rates decreased as much as 50% within 24 h of raising the fat content in the diet to 60% of the caloric intake. These rates eventually returned to normal values after 2-3 wk on the HF regimen, seemingly to prevent further IMCL accumulation. Only beyond 1 mo on the HF diet did results consistently show ATP synthesis rates to diminish by 30-50% accompanied by steadily augmenting IMCL levels. Interestingly, switching back to a chow diet after 3 wk of HF feeding reversed the initial diet-induced changes. Although the muscle mitochondrial system may initially offer enough compliance to counteract lipid surplus, these in vivo data suggest a vicious long-term cycle among mitochondrial dysfunction, IMCL accumulation, and glucose intolerance in the rat.

Women with learning disability and uptake of screening: audit of screening uptake before and after one to one counselling.

BACKGROUND: This study investigates the breast and cervical screening status of women with moderate to severe learning disability and whether uptake could be improved by one to one counselling. METHODS: An audit of screening uptake of women in contact with the National Health Service (NHS) learning disability service within the eligible age groups for breast and cervical screening before and after one to one counselling by a learning disability team nurse. RESULTS: Of the eligible 48 women, 37 (77 per cent) had undergone breast screening indicating that uptake was excellent and comparable to the average national and local uptake. As for cervical screening, of the 160 women who were identified as eligible and were contactable, only 26 (16 per cent) were having regular smear tests. At the end of the project, which involved one to one counselling by the nurses to encourage uptake, nine additional women underwent smear tests bringing the uptake rate to 22 per cent. For the remaining 96 women (60 per cent) the reasons at the time for non-uptake were recognized as appropriate. CONCLUSIONS: Although the uptake of breast screening was found to be good, cervical screening uptake for women with learning disability was low and remained low after a supportive intervention designed to increase uptake. The greater acceptability of breast screening in women with moderate to severe learning disability compared to cervical screening has been confirmed.

Age and muscle-type modulated role of intramyocellular lipids in the progression of insulin resistance in nondiabetic Zucker rats.

The effect of muscle fiber type and maturation on intramyocellular lipid (IMCL) content and its relationship to insulin resistance was investigated. Intramyocellular lipid content in slow-twitch (soleus) and fast-twitch (tibialis anterior, TA) muscles of fa/fa (Zucker fatty rat, ZFR) and age-matched lean (Zucker lean rat, ZLR) Zucker rats were repeatedly measured over 3 months. Intramyocellular lipid levels in both the soleus and the TA were significantly higher in the ZFR relative to the ZLR. For the ZFR, IMCL TA increased by approximately 2-fold from 5.3 to 8.4 weeks of age. No subsequent accumulation of IMCL TA occurred in ZFR from 8.4 up to 13.1 weeks of age. For ZLR, IMCL TA contents steadily decreased from 6.6 to 13.1 weeks of age (-77%, P<.05). In contrast, IMCL levels in the soleus were not significantly altered in either rat strain over the course of the study. Maximum impairment in whole-body insulin sensitivity in ZFR was observed at 9-weeks of age, concomitant with peak IMCL TA accumulation. Insulin-stimulated 2-deoxy-D-glucose (2DG) transport in the TA muscle of 10.2- and 14.1-week-old ZFR was significantly impaired relative to age-matched ZLR. Insulin-stimulated glucose uptake in the soleus of ZFR and ZLR decreased (P<.05) as the animals matured (ZFR, -49%; ZLR, -69%). Overall, these results support the hypothesis that fast-twitch glycolytic muscles play a major role during the onset of insulin resistance. In addition, proper timing may govern the success of a pharmacological studies aimed at measuring the impact of insulin-sensitizing drugs on IMCL.