Treatment choice, medication adherence and glycemic efficacy in people with type 2 diabetes: a UK clinical practice database study

Objective Using primary care data obtained from the UK Clinical Practice Research Datalink, this retrospective cohort study examined the relationships between medication adherence and clinical outcomes in patients with type 2 diabetes. Research design and methods Data were extracted for patients treated between 2008 and 2016, and stratified by oral antihyperglycemic agent (OHA) line of therapy (mono, dual or triple therapy). Patients were monitored for up to 365 days; associations between medication possession ratio (MPR) and outcomes at 1 year (glycated hemoglobin A1c (HbA1c), weight and hypoglycemia incidence) were assessed using linear regression modeling and descriptive analyses. Results In total, 33 849 patients were included in the study (n=23 925 OHA monotherapy; n=8406 OHA dual therapy; n=1518 OHA triple therapy). One-year change in HbA1c was greater among adherent (−0.90 to −1.14%; −9.8 to −12.5 mmol/mol) compared with non-adherent patients (−0.49 to −0.69%; −5.4 to −7.5 mmol/mol). On average, adherent patients had higher hypoglycemia event rates than non-adherent patients (rate ratios of 1.24, 1.10 and 2.06 for OHA mono, dual and triple therapy cohorts, respectively) and experienced greater weight change from baseline. A 10% improvement in MPR was associated with −0.09% (−1.0 mmol/mol), −0.09% (−1.0 mmol/mol) and −0.21% (−2.3 mmol/mol) changes in HbA1c for OHA mono, dual and triple therapy cohorts, respectively. Conclusions For patients with type 2 diabetes, increasing medication adherence can bring about meaningful improvements in HbA1c control as the requirement for treatment escalation increases. Regimens associated with weight loss and the avoidance of hypoglycemia were generally associated with better medication adherence and improved glycemic control

Switching from premixed insulin to glargine-based insulin regimen improves glycaemic control in patients with type 1 or type 2 diabetes: a retrospective primary care-based analysis

Background: Insulin glargine (glargine) and premixed insulins (premix) are alternative insulin treatments. This analysis evaluated glycaemic control in 528 patients with type 1 (n = 183) or type 2 (n = 345) diabetes, after switching from premix to a glargine-based regimen, using unselected general practice (GP) data. Methods: Data for this retrospective observational analysis were extracted from a UK GP database (The Health Improvement Network). Patients were required to have at least 12 months of available data, before and after, switching from premix to a glargine-based regimen. The principal analysis was the change in HbA1c after 12 months of treatment with glargine; secondary analyses included change in weight, bolus usage and total daily insulin dose. Inconsistent reporting of hypoglycemic episodes precludes reliable assessment of this outcome. Multivariate analyses were used to adjust for baseline characteristics and confounding variables. Results: Both cohorts showed significant reduction in mean HbA1c 12 months after the switch: by -0.67% (p < 0.001) in the type 1 cohort and by -0.53% (p < 0.001) in the type 2 cohort (adjusted data). The size of HbA1c improvement was positively correlated with baseline HbA1c; patients with a baseline HbA1c ≥ 10% had the greatest mean reduction in HbA1c, by -1.7% (p < 0.001) and -1.2% (p < 0.001), respectively. The proportion of patients receiving co-bolus prescriptions increased in the type 1 (mean 24.6% to 95.1%, p < 0.001) and type 2 (mean 16.2% to 73.9%, p < 0.001) cohorts. There was no significant change in weight in either cohort. Total mean insulin use increased in type 2 diabetes patients (from 0.67 ± 1.35 U/Kg to 0.88 ± 1.33 U/Kg, p < 0.001) with a slight decrease in type 1 diabetes patients (from 1.04 ± 2.51 U/Kg to 0.98 ± 2.58 U/Kg, p < 0.001). Conclusion: In everyday practice, patients with type 1 or type 2 diabetes inadequately controlled by premix insulins experienced significant improvement in glycaemic control over 12 months after switching to a glargine-based insulin regimen. These findings support the use of a basal-bolus glargine-based regimen in patients poorly controlled on premix.Peter Sharplin, Jason Gordon, John R Peters, Anthony P Tetlow, Andrea J Longman and Philip McEwa

Early adopters versus the majority: characteristics and implications for academic development and institutional change

The concept of early adoptersversus mainstream majority has become common parlance when considering the uptake of technology-enhanced learning and teaching (TELT) in higher education, and relates to the readiness with which individuals adopt new technologies.This study used a questionnaire to explore the views and experiences of staff at one research-led institution within one of four colleges, to determine whether there were differences between the characteristics and digital academic practices of teachers, based on their self-identification as one of five types of technology adopters (innovators, early adopters, early majority, late majority and laggards). Subsequently, two focus groups allowed comparisons between early adopters and early majoritystaff.Thequestionnaire found differencesbetween the groupsin relation tousing a VLE to foster deep thinking through discussion, teachers’ digital practices and attributes, previous engagement with developmental TELTopportunities, perceived level of support from management, and perceived usefulness of continued professional development (CPD)opportunities. Focus groups revealed qualitative differences in terms of the amount of time participants invested in learning new technologies, sources of TELTsupport, preference for different types of academic development, and how they engaged with exemplars in their own or other disciplines.In addition to recommendations for different types of academic development for different groups, the study highlighted the importance of early adopters in leading digital practice. Institutions need to recognise and support the unique contribution made by early adopters. They contribute to the resilience, agility and digital capabilities of an institution in responding to rapid changes, such as the Covid19 pandemic, in terms of supporting and leading other staff, and prompting the institution to expand its digital education infrastructure

A Transgenic Mouse Line Expressing Cre Recombinase in Undifferentiated Postmitotic Mouse Retinal Bipolar Cell Precursors

Approaches for manipulating cell type-specific gene expression during development depend on the identification of novel genetic tools. Here, we report the generation of a transgenic mouse line that utilizes Vsx2 upstream sequences to direct Cre recombinase to developing retinal bipolar cells. In contrast to the endogenous Vsx2 expression pattern, transgene expression was not detected in proliferating retinal progenitor cells and was restricted to post-mitotic bipolar cells. Cre immunolabeling was detected in rod bipolar cells and a subset of ON and OFF cone bipolar cells. Expression was first observed at postnatal day 3 and was detectable between 24 hours and 36 hours after the last S-phase of the cell cycle. The appearance of Cre-immunolabeled cells preceded the expression of bipolar cell type-specific markers such as PKCα and Cabp5 suggesting that transgene expression is initiated prior to terminal differentiation. In the presence of a constitutive conditional reporter transgene, reporter fluorescence was detected in Cre-expressing bipolar cells in the mature retina as expected, but was also observed in Cre-negative Type 2 bipolar cells and occasionally in Cre-negative photoreceptor cells. Together these findings reveal a new transgenic tool for directing gene expression to post-mitotic retinal precursors that are mostly committed to a bipolar cell fate

The Composition and Metabolic Phenotype of Neisseria gonorrhoeae Biofilms

Neisseria gonorrhoeae has been shown to form biofilms during cervical infection. Thus, biofilm formation may play an important role in the infection of women. The ability of N. gonorrhoeae to form membrane blebs is crucial to biofilm formation. Blebs contain DNA and outer membrane structures, which have been shown to be major constituents of the biofilm matrix. The organism expresses a DNA thermonuclease that is involved in remodeling of the biofilm matrix. Comparison of the transcriptional profiles of gonococcal biofilms and planktonic runoff indicate that genes involved in anaerobic metabolism and oxidative stress tolerance are more highly expressed in biofilm. The expression of aniA, ccp, and norB, which encode nitrite reductase, cytochrome c peroxidase, and nitric oxide reductase respectively, is required for mature biofilm formation over glass and human cervical cells. In addition, anaerobic respiration occurs in the substratum of gonococcal biofilms and disruption of the norB gene required for anaerobic respiration, results in a severe biofilm attenuation phenotype. It has been demonstrated that accumulation of nitric oxide (NO) contributes to the phenotype of a norB mutant and can retard biofilm formation. However, NO can also enhance biofilm formation, and this is largely dependent on the concentration and donation rate or steady-state kinetics of NO. The majority of the genes involved in gonococcal oxidative stress tolerance are also required for normal biofilm formation, as mutations in the following genes result in attenuated biofilm formation over cervical cells and/or glass: oxyR, gor, prx, mntABC, trxB, and estD. Overall, biofilm formation appears to be an adaptation for coping with the environmental stresses present in the female genitourinary tract. Therefore, this review will discuss the studies, which describe the composition and metabolic phenotype of gonococcal biofilms

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction:A pooled analysis of DAPA-HF and DELIVER data

Aim: To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). Methods and results: Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. Conclusions: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.</p

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction:A pooled analysis of DAPA-HF and DELIVER data

Aim: To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). Methods and results: Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. Conclusions: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.</p

Does the book have a future?

Advances in technology have produced a range of devices on which a book can be read, from an e‐book reader to a tablet or phone. E‐books have the advantages that a reader can take a sizeable selection when traveling, read backlit text, and enlarge the type size to suit. The book exists in both printed and digital form, as p‐book and e‐book. Digital technology has also revolutionized the production of printed books. Digital printing, as opposed to traditional offset printing, enables genuine print on demand as well as short runs. This facility has less relevance to the world of mass‐market paperbacks, where large print runs mean that the benefits of offset printing still apply, but it is of great interest to most publishers and those who want to self‐publish. In fact, more books are published than ever before, and there has been a boom in self‐publishing

What do older people do when sitting and why? Implications for decreasing sedentary behaviour

Background and Objectives: Sitting less can reduce older adults’ risk of ill health and disability. Effective sedentary behavior interventions require greater understanding of what older adults do when sitting (and not sitting), and why. This study compares the types, context, and role of sitting activities in the daily lives of older men and women who sit more or less than average. Research Design and Methods: Semistructured interviews with 44 older men and women of different ages, socioeconomic status, and objectively measured sedentary behavior were analyzed using social practice theory to explore the multifactorial, inter-relational influences on their sedentary behavior. Thematic frameworks facilitated between-group comparisons. Results: Older adults described many different leisure time, household, transport, and occupational sitting and non-sitting activities. Leisure-time sitting in the home (e.g., watching TV) was most common, but many non-sitting activities, including “pottering” doing household chores, also took place at home. Other people and access to leisure facilities were associated with lower sedentary behavior. The distinction between being busy/not busy was more important to most participants than sitting/not sitting, and informed their judgments about high-value “purposeful” (social, cognitively active, restorative) sitting and low-value “passive” sitting. Declining physical function contributed to temporal sitting patterns that did not vary much from day-to-day. Discussion and Implications: Sitting is associated with cognitive, social, and/or restorative benefits, embedded within older adults’ daily routines, and therefore difficult to change. Useful strategies include supporting older adults to engage with other people and local facilities outside the home, and break up periods of passive sitting at home

The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury

Activation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.The work was supported by the National Institutes of Health grants (R01NS110825 and R01NS088627) to L.J.W and National Research Founda‑tion of Korea grants (NRF-2017M3C7A1025602, 2018R1A5A2024418 and 2021R1A2C3003334) from Korean government MSIT (Ministry of Science and ICT) to S.B.O