Pre-diabetes in the elderly and the see-saw model of paternalism.

Pre-diabetes is a risk factor for the development of diabetes, not a disease in its own right. The prevalence increases with age and reaches nearly 50% of those aged over 75 years in the USA. While lifestyle modification and treatment are likely to benefit those with many years of life ahead of them, they are unlikely to benefit patients with a limited life expectancy. Despite this, some very elderly patients in the UK and elsewhere are being labelled as pre-diabetic. While ideal practice would be to carefully consider the impact of any potentially abnormal blood test before it is taken, this is not always possible in routine practice. In this paper, we discuss a pragmatic, ethical approach for clinicians managing pre-diabetic blood tests in very elderly patients. We argue that a 'see-saw' model of paternalism should be used in deciding which patients to inform that they can be labelled as pre-diabetic. Those patients that may benefit from the label should be informed, and those that will not, should not. Where the benefits/drawbacks are unclear, the result and its potential significance should be discussed in depth with the individual patient. We do not advocate withholding information from any patient. Instead we suggest clinicians use individual patient circumstances to contextualise the relevance of pre-diabetes to the patient and consider the benefits and drawbacks before informing them. This approach has the potential to be used for other pre-conditions and risk factors in addition to pre-diabetes.

Understanding the diagnosis of pre-diabetes in patients aged over 85 in English primary care: a qualitative study.

BACKGROUND: The benefit of a "diagnosis" of pre-diabetes in very elderly patients is debated. How clinicians manage pre-diabetic blood results in these patients is unknown. This study aims to understand how clinicians are "diagnosing" older patients with pre-diabetic blood parameters. METHODS: Semi-structured interviews and focus groups with health care staff (24 total participants) were conducted in the north of England. Interviews and focus groups were recorded, transcribed and analysed thematically. A grounded theory approach was taken with the theory of candidacy being used as a sensitising concept through which questions were framed and results interpreted. RESULTS: There is a complex system of competing pressures that influence a clinician in deciding whether, and in what way, to inform a very elderly patient that they have pre-diabetes. The majority of clinicians adjust their management of pre-diabetes to the age and perceived risk/benefit for the patient. Whilst some clinicians choose not to inform certain patients of their blood results, many clinicians maintain, what could be seen as a somewhat paradoxical approach of labeling all older patients with pre-diabetes but downplaying the significance to the patient. The policy, organisational context, workload and professional constraints under which clinicians work, play a significant role in shaping how they deal with pre-diabetic blood results in the very elderly. CONCLUSION: There has been recent acknowledgement of how policy and organisational context frames decision-making, but there is a lack of evidence on how this influences uncertainty and dilemmas in decision-making in practice. These findings add further weight for the argument that treatment burden should be included in clinical guidelines.

EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer.

BACKGROUND AND AIMS: Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy. METHODS: In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death. RESULTS: Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection. CONCLUSIONS: Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.

Biological evaluation of pyridone alkaloids on the endocannabinoid system.

Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10µM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.

Impact of diabetes mellitus on clinical outcomes in patients undergoing surgical resection for pancreatic cancer: a retrospective, cohort study.

OBJECTIVES: Diabetes mellitus (DM) has a bidirectional association with pancreatic cancer (PaC); however, its effect on clinical outcomes has not been thoroughly evaluated. We analyzed these data in a large sample of PaC subjects who had undergone surgical resection. METHODS: Subjects enrolled in the Mayo Clinic Pancreatic Cancer SPORE registry from 2000 to 2010 who had resection with curative intent were identified (n=488). Tumor size, cancer stage, and postoperative median survival were evaluated. Median survivals were compared with Kaplan-Meier curves and Cox proportional hazards regression modeling. RESULTS: A total of 275 (56%) subjects had DM before surgery. DM subjects had larger tumors compared with those without DM (3.6 cm vs. 3.3, P=0.002), even after controlling for covariates including age, body mass index, and tumor grade. Cancer stage at the time of surgery was not affected by DM status (P=0.575). Preoperative DM was not associated with an increased risk of death using a multivariable survival analysis (hazard ratio 1.06, 95% confidence interval 0.81-1.38, P=0.676). The median survival following cancer resection was similar between subjects with and without DM (24 vs. 26 months, P=0.610). In addition, postoperative survival was similar on the basis of the duration of DM (new-onset vs. long-standing) and prior use of antidiabetic treatments in diabetic subjects. CONCLUSIONS: PaC subjects with DM have larger tumors than nondiabetic subjects. Despite this observation, preoperative DM does not negatively impact the cancer stage at the time of surgery or postoperative survival. Thus, the effect of DM on tumor size is either overshadowed by early metastatic spread of the cancer or is mitigated by the tumor resection.

Patient reported measures of continuity of care and health outcomes: a systematic review.

BACKGROUND: There is a considerable amount of research showing an association between continuity of care and improved health outcomes. However, the methods used in most studies examine only the pattern of interactions between patients and clinicians through administrative measures of continuity. The patient experience of continuity can also be measured by using patient reported experience measures. Unlike administrative measures, these can allow elements of continuity such as the presence of information or how joined up care is between providers to be measured. Patient experienced continuity is a marker of healthcare quality in its own right. However, it is unclear if, like administrative measures, patient reported continuity is also linked to positive health outcomes. METHODS: Cohort and interventional studies that examined the relationship between patient reported continuity of care and a health outcome were eligible for inclusion. Medline, EMBASE, CINAHL and the Cochrane Library were searched in April 2021. Citation searching of published continuity measures was also performed. QUIP and Cochrane risk of bias tools were used to assess study quality. A box-score method was used for study synthesis. RESULTS: Nineteen studies were eligible for inclusion. 15 studies measured continuity using a validated, multifactorial questionnaire or the continuity/co-ordination subscale of another instrument. Two studies placed patients into discrete groups of continuity based on pre-defined questions, one used a bespoke questionnaire, one calculated an administrative measure of continuity using patient reported data. Outcome measures examined were quality of life (n = 11), self-reported health status (n = 8), emergency department use or hospitalisation (n = 7), indicators of function or wellbeing (n = 6), mortality (n = 4) and physiological measures (n = 2). Analysis was limited by the relatively small number of hetrogenous studies. The majority of studies showed a link between at least one measure of continuity and one health outcome. CONCLUSION: Whilst there is emerging evidence of a link between patient reported continuity and several outcomes, the evidence is not as strong as that for administrative measures of continuity. This may be because administrative measures record something different to patient reported measures, or that studies using patient reported measures are smaller and less able to detect smaller effects. Future research should use larger sample sizes to clarify if a link does exist and what the potential mechanisms underlying such a link could be. When measuring continuity, researchers and health system administrators should carefully consider what type of continuity measure is most appropriate.

Factors affecting the experience of joined-up, continuous primary care in the absence of relational continuity: an observational study.

BACKGROUND: There is an international trend towards the at-scale provision of primary care services, with such services often provided in different settings by a clinician unfamiliar to the patient. It is often assumed that, in the absence of relational continuity, any competent clinician can deliver joined-up, continuous care if they have access to clinical notes. AIM: To explore the factors that affect the potential for providing joined-up, continuous care in a system where care is delivered away from a patient's regular practice, by a different organisation and set of staff. DESIGN AND SETTING: Case studies of two extended-access providers in the north of England. METHOD: Case studies were carried out between September 2021 and January 2022 in two sites. Data collected included observations of patient-healthcare professional interactions, interviews with staff and patients, and documentation. Analysis took place using a constant comparison approach. Data were coded. A model of the factors affecting continuity was constructed. RESULTS: The potential for joined-up, continuous care appears dependent on staff, patient, and system factors. This includes diverse elements such as the attitude of clinicians to care coordination and the ability of an organisation to retain staff. CONCLUSION: Healthcare systems increasingly rely on the assumption that any competent clinician can deliver joined-up, continuous care if they have access to clinical notes. This appears not to be the case. This study presents a model of factors affecting the patient's experience of continuity. The model needs validating in in-hours general practice and other settings.

Delivering relational continuity of care in UK general practice: a scoping review.

BACKGROUND: Relational continuity of care (patients seeing the same GP) is associated with better outcomes for patients, but it has been declining in general practice in the UK. AIM: To understand what interventions have been tried to improve relational continuity of care in general practice in the UK. DESIGN & SETTING: Scoping review of articles on UK General Practice and written in English. METHOD: An electronic search of MEDLINE, Embase, and Scopus from 2002 to the present day was undertaken. Sources of grey literature were also searched. Studies that detailed service-level methods of achieving relational continuity of care with a GP in the UK were eligible for inclusion. Interventions were described narratively in relation to the elements listed in the Template for Intervention Description and Replication (TIDieR). A logic model describing the rationale behind interventions was constructed. RESULTS: Seventeen unique interventions were identified. The interventions used a wide variety of strategies to try to improve relational continuity. This included personal lists, amended booking processes, regular reviews, digital technology, facilitated follow-ups, altered appointment times, and use of acute hubs. Twelve of the interventions targeted specific patient groups for increased continuity while others focused on increasing continuity for all patients. Changes in continuity levels were measured inconsistently using several different methods. CONCLUSION: Several different strategies have been used in UK general practices in an attempt to improve relational continuity of care. While there is a similar underlying logic to these interventions, their scope, aims, and methods vary considerably. Furthermore, owing to a weak evidence base, comparing their efficacy remains challenging.

Caged retinoids as photoinducible activators: implications for cell differentiation and neurite outgrowth.

Aiming to control neurite formation and navigate the axonal growth by an extrinsic guidance, we report on the design, synthesis and biological evaluation of caged retinoids. Agonists of RARß have been temporarily blocked either by the [(α-methyl-2-nitropiperonyl)oxy]carbonyl (MeNPOC) group or by immobilization using nitrocatechol linkers on TiO2 particles. Release on demand has been achieved by release under UV irradiation, leading to the biologically active compounds, which have been shown to induce neuronal differentiation and neurite outgrowth.

Has the NHS national extended access scheme delivered its policy aims? A case study of two large scale extended access providers.

OBJECTIVES: In 2018, NHS England mandated that all patients in England should be able to access general practice services outside of ordinary hours. While some patients would access additional hours at their own practice, others would need supra-practice level provision - that is, they would be seen in a different location and by a different care team. The policy aim was to enhance patient access to care, with a particular focus on those who work during the day. This study examines (a) how supra-practice level provision of extended access appointments for general medical problems are operationalised and (b) whether the aims of the policy are being met. METHODS: This study presents qualitative comparative case studies of two contrasting service providers offering extended access. The data collected included 30 hours of clinician-patient observations, 25 interviews with staff, managers, and commissioners, 20 interviews with patients, organisational protocols/documentation, and routinely collected appointment data. Thematic analysis ran concurrently with data gathering and facilitated the iterative adaptation of data collection. RESULTS: Three cross-cutting themes were identified: extended access is being used to bolster a struggling primary care system, extended access provides a different service to in-hours general practice, and it is difficult for extended access to provide seamless care. CONCLUSIONS: Supra-practice access models can provide effective care for most patients with straightforward issues. When ongoing management of complex problems is required, this model of patient care can be problematic.

Exploring the impact of the national extended access scheme on patient experience of and satisfaction with general practice: an observational study using the English GP Patient Survey.

BACKGROUND: Extended access services were introduced to help stop declining patient satisfaction with access to general practice. There has been no evaluation, at a practice population level, as to how the introduction of these services has impacted patients. AIM: To explore the association between practices offering extended access and patient responses to the GP Patient Survey (GPPS). DESIGN & SETTING: An observational study was carried out. Patient experience data were taken from the national GPPS in England (2018 and 2019). Data on the provision of extended access services were sourced from NHS England. The analyses considered potential confounding factors. These were sourced from publicly available data about practice characteristics from NHS Digital, NHS England, and government websites. METHOD: The percentage of patients reporting positive responses to questions related to satisfaction with access, continuity of care, and overall satisfaction were modelled. The association between these outcomes and the provision of extended access were estimated via multivariable fixed-effects linear regression. RESULTS: There were no associations between practices offering extended access services and key indicators of patient experience or satisfaction at a practice population level. CONCLUSION: Extended access has a cost of an estimated 250 million GBP per year. While there is a body of work that finds associations with emergency department use reduction, at a practice population level, in this study it has been found that extended access had no measurable impact. This may be because extended access services are only used by a small number of patients, and its introduction has not significantly impacted general practices and most general practice patients.

The Role of Interstitial Fluid Pressure in Cerebral Porous Biomaterial Integration.

Recent advances in biomaterials offer new possibilities for brain tissue reconstruction. Biocompatibility, provision of cell adhesion motives and mechanical properties are among the present main design criteria. We here propose a radically new and potentially major element determining biointegration of porous biomaterials: the favorable effect of interstitial fluid pressure (IFP). The force applied by the lymphatic system through the interstitial fluid pressure on biomaterial integration has mostly been neglected so far. We hypothesize it has the potential to force 3D biointegration of porous biomaterials. In this study, we develop a capillary hydrostatic device to apply controlled in vitro interstitial fluid pressure and study its effect during 3D tissue culture. We find that the IFP is a key player in porous biomaterial tissue integration, at physiological IFP levels, surpassing the known effect of cell adhesion motives. Spontaneous electrical activity indicates that the culture conditions are not harmful for the cells. Our work identifies interstitial fluid pressure at physiological negative values as a potential main driver for tissue integration into porous biomaterials. We anticipate that controlling the IFP level could narrow the gap between in vivo and in vitro and therefore decrease the need for animal screening in biomaterial design.

An Injectable Meta-Biomaterial: From Design and Simulation to In Vivo Shaping and Tissue Induction.

A novel type of injectable biomaterial with an elastic softening transition is described. The material enables in vivo shaping, followed by induction of 3D stable vascularized tissue. The synthesis of the injectable meta-biomaterial is instructed by extensive numerical simulation as a suspension of irregularly fragmented, highly porous sponge-like microgels. The irregular particle shape dramatically enhances yield strain for in vivo stability against deformation. Porosity of the particles, along with friction between internal surfaces, provides the elastic softening transition. This emergent metamaterial property enables the material to reversibly change stiffness during deformation, allowing native tissue properties to be matched over a wide range of deformation amplitudes. After subcutaneous injection in mice, predetermined shapes can be sculpted manually. The 3D shape is maintained during excellent host tissue integration, with induction of vascular connective tissue that persists to the end of one-year follow-up. The geometrical design is compatible with many hydrogel materials, including cell-adhesion motives for cell transplantation. The injectable meta-biomaterial therefore provides new perspectives in soft tissue engineering and regenerative medicine.

Injectable, scalable 3D tissue-engineered model of marrow hematopoiesis.

Modeling the interaction between the supportive stroma and the hematopoietic stem and progenitor cells (HSPC) is of high interest in the regeneration of the bone marrow niche in blood disorders. In this work, we present an injectable co-culture system to study this interaction in a coherent in vitro culture and in vivo transplantation model. We assemble a 3D hematopoietic niche in vitro by co-culture of supportive OP9 mesenchymal cells and HSPCs in porous, chemically defined collagen-coated carboxymethylcellulose microscaffolds (CCMs). Flow cytometry and hematopoietic colony forming assays demonstrate the stromal supportive capacity for in vitro hematopoiesis in the absence of exogenous cytokines. After in vitro culture, we recover a paste-like living injectable niche biomaterial from CCM co-cultures by controlled, partial dehydration. Cell viability and the association between stroma and HSPCs are maintained in this process. After subcutaneous injection of this living artificial niche in vivo, we find maintenance of stromal and hematopoietic populations over 12 weeks in immunodeficient mice. Indeed, vascularization is enhanced in the presence of HSPCs. Our approach provides a minimalistic, scalable, biomimetic in vitro model of hematopoiesis in a microcarrier format that preserves the HSPC progenitor function, while being injectable in vivo without disrupting the cell-cell interactions established in vitro.

Regional variation and predictors of over-registration in English primary care in 2014: a spatial analysis.

BACKGROUND: There are more people registered with a general practice in England than are estimated to be resident in the country. The reasons behind this are not fully understood. We investigated the levels of over-registration (or under-registration) in English primary care, their regional variability and their association with population and geographical characteristics. METHODS: This was a cross-sectional study using mid-year population estimates for 2014 and general practice populations for the same year. We calculated levels of patient registration with English primary care, in relation to census-derived population estimates, at various geographical levels of interest: regions, clinical commissioning groups and lower super output areas (LSOAs, 2011 census derived geographical areas of 1500 people on average). We used linear regressions to investigate the relationship between levels of registration and area deprivation, urbanicity, ethnicity, age, sex and mean distance to practice. RESULTS: The total over-registration rate for England was 3.9% (2 097 101 people) but there was wide regional variability. London had significantly higher levels of over-registration (6.0% and 515 063 people) than other areas in England. Higher levels of over-registration at the LSOA level were associated with greater proportions of non-White British residents, women, elderly people and higher levels of social deprivation. CONCLUSION: Our findings indicate that high mobility and health need may be the underlying causes of over-registrations. The regional variation in over-registration, with London being an outlier, points towards potential inequalities in resourcing of primary care and the ability of the National Health Service to adequately match funding to population need.

Injectable dynamic covalent hydrogels of boronic acid polymers cross-linked by bioactive plant-derived polyphenols.

We report here the development of hydrogels formed at physiological conditions using PEG (polyethylene glycol) based polymers modified with boronic acids (BAs) as backbones and the plant derived polyphenols ellagic acid (EA), epigallocatechin gallate (EGCG), tannic acid (TA), nordihydroguaiaretic acid (NDGA), rutin trihydrate (RT), rosmarinic acid (RA) and carminic acid (CA) as linkers. Rheological frequency sweep and single molecule force spectroscopy (SMFS) experiments show that hydrogels linked with EGCG and TA are mechanically stiff, arising from the dynamic covalent bond formed by the polyphenol linker and boronic acid functionalized polymer. Stability tests of the hydrogels in physiological conditions revealed that gels linked with EA, EGCG, and TA are stable. We furthermore showed that EA- and EGCG-linked hydrogels can be formed via in situ gelation in pH 7.4 buffer, and provide long-term steady state release of bioactive EA. In vitro experiments showed that EA-linked hydrogel significantly reduced the viability of CAL-27 human oral cancer cells via gradual release of EA.

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.