Diabetes and Covid-19: Diabetes research funding and support during the pandemic.

AIMS: Between late 2020 and early 2022, EURADIA undertook a survey of organisations and individuals supporting or working in the field of diabetes research with the aim of understanding better the impact of the Covid-19 pandemic on funding for diabetes research in Europe. METHODS: Information was collected via online survey augmented in some cases by face-to-face interviews. RESULTS: Findings were mixed but the majority of those responding suggested a moderate impact of the pandemic on diabetes research activity. Many respondents reported a reduction in funding during the pandemic and many of those involved in clinical research experienced a reduction in research clinicians' availability for diabetes research as they were redeployed to Covid-19 patient care. It was frequently reported that the impact might not be fully appreciated until several years after the end of the pandemic. CONCLUSIONS: This preliminary survey suggests there may be a significant impact of the pandemic on all aspects of diabetes research and that a more detailed follow-up on the impact of the pandemic on funding of diabetes research should be carried out in the future.

Bringing the patient's perspectives forward in drug development and health-care evaluation.

INTRODUCTION: For many years, psychologists and other social scientists have been pushing for the individual patient's perspective - priorities, needs, feelings, and functioning - to be incorporated into drug development. This is usually achieved through the use of patient-reported outcome measures (PROMs) in clinical trials. AREAS COVERED: This paper discusses some key issues in the use of PROM data as the sole method of generating information about the patient's perspective and outlines the relevance of narrative evidence to enhance understanding and interpretation of PROM data. EXPERT OPINION: The development and use of PROMs situates them at the vertex of two very different trends in medicine: patient-centered care and standardization. Indeed, the application of PROMs - which pull in the direction of standardization - results in a narrow conception of evidence by overriding the subjectivity of individual experiences, beliefs, and judgments. Without additional context, PROM data cannot easily support individual patient-level care. When collected systematically and with an interpretive phenomenological approach, narrative data can contain valuable information about the patient experience that numerical ratings from PRO measures do not capture.

Developing a questionnaire to determine the impact of self-management in diabetes: giving people with diabetes a voice.

BACKGROUND: The prevalence of diabetes mellitus (DM) is increasing dramatically, placing considerable financial burden on the healthcare budget of each country. Patient self-management is crucial for the control of blood glucose, which largely determines the chances of developing diabetes-related complications. Self-management interventions vary widely, and a method is required for assessing the impact of self-management. This paper describes the development of a questionnaire intended for use to measure the impact of self-management in diabetes. METHODS: An iterative development process was undertaken to identify the attributes of self-management using 5 steps. First, a literature review was undertaken to identify and understand themes relating to self-management of DM to inform a topic guide. Second, the topic guide was further refined following consultation with a Patient and Public Involvement group. Third, the topic guide was used to inform semi-structured interviews with patients with Type 1 DM (T1DM) and Type 2 DM (T2DM) to identify how self-management of DM affects individuals. Fourth, the research team considered potential attributes alongside health attributes from an existing measure (Diabetes Health Profile, DHP) to produce an instrument reflecting both health and self-management outcomes simultaneously. Finally, a draft instrument was tested in a focus group to determine the wording and acceptability. RESULTS: Semi-structured interviews were carried out with 32 patients with T1DM and T2DM. Eight potential attributes were identified: fear/worry/anxiety, guilt, stress, stigma, hassle, control, freedom, and feeling supported. Four of these self-management attributes were selected with four health attributes (mood, worry about hypos (hypoglycaemic episodes), vitality and social limitations) to produce the Health and Self-Management in Diabetes (HASMIDv1) questionnaire. CONCLUSIONS: HASMIDv1 is a short questionnaire that contains eight items each with four response levels to measure the impact of self-management in diabetes for both T1DM and T2DM. The measure was developed using a mixed-methods approach that involved semi-structured interviews with people with diabetes. The measure has high face validity. Ongoing research is being undertaken to assess the validity of this questionnaire for measuring the impact of self-management interventions in economic evaluation.

Developing preference-based measures for diabetes: DHP-3D and DHP-5D.

AIMS: The aim of this study was to develop two diabetes-specific preference-based measures [the Diabetes Health Profile-3 Dimension (DHP-3D) and the Diabetes Health Profile-5 Dimension (DHP-5D)] for use in the calculation of Quality Adjusted Life Years, a key outcome in economic evaluation. These measures were based on the non-preference-based instrument the Diabetes Health Profile. METHODS: For DHP-3D, psychometric and Rasch analyses were used to develop a health state classification system based on the Diabetes Health Profile-18 (DHP-18). The DHP-5D added two dimensions to the DHP-3D to extend the range of impacts measured. Each classification system was valued by 150 general public respondents in the United Kingdom using Time Trade Off (TTO). Multivariate regression was used to estimate utility value sets. The matched dimensions across each measure were compared using z-score tests. RESULTS: The DHP-3D included three dimensions defined as mood, eating and social limitations, and the DHP-5D added dimensions defined as hypoglycaemic attacks and vitality. For both, the random effects generalized least squares regression model produced consistent value sets, with the DHP-3D and DHP-5D ranging from 0.983 (best state) to 0.717 (worst state), and 0.979 to 0.618 respectively. The addition of the two extra dimensions leads to significant differences for the more severe levels of each matched dimension. CONCLUSIONS: We have developed two diabetes-specific preference-based measures that, subject to psychometric assessment, can be used to provide condition-specific utility values to complement generic utilities from more widely validated measures such as the EuroQol-5 Dimension.

Treatment of facial erythema in patients with rosacea with topical brimonidine tartrate: correlation of patient satisfaction with standard clinical endpoints of improvement of facial erythema.

BACKGROUND: Once-daily brimonidine tartrate (BT) 0.5% gel was shown to provide significantly greater efficacy vs. vehicle for the treatment of facial erythema in patients with rosacea. OBJECTIVES: To demonstrate that patient satisfaction with overall appearance is correlated with reduction in facial erythema, as measured by clinician and patient assessments. METHODS: Data from two identical phase III, multicentre, randomized, controlled trials of moderate facial erythema of rosacea (study A: n = 260; study B: n = 293) with topical BT 0.5% compared to vehicle gel once-daily for 4 weeks were analysed. Correlations of Patient's Assessment of Appearance (PAA) with Clinician's Erythema Assessment (CEA) and Patient's Self-Assessment (PSA) of erythema were evaluated by calculation of gamma statistics. RESULTS: PAA correlated with CEA post-application on Days 1, 15 and 29 for the intent-to-treat population and provided a median gamma value of 0.57 (min = 0.28, max = 0.61). PAA and PSA was also highly correlated post-application on Days 1, 15 and 29; with a median gamma value of 0.87 (min = 0.66, max = 0.89). Subjects who achieved a clinically meaningful improvement in both CEA and PSA scales were more likely to report satisfaction with the overall appearance of their skin (P < 0.001). CONCLUSIONS: Both one- and two-grade improvements in facial erythema assessed by subjects (PSA) and clinicians (CEA) correlate well with PAA, a patient-centered representation of meaningful change.

Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats.

Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging.

Once-daily topical brimonidine tartrate gel 0·5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies.

BACKGROUND: Erythema of rosacea is thought to result from abnormal cutaneous vasomotor activity. Brimonidine tartrate (BT) is a highly selective α(2) -adrenergic receptor agonist with vasoconstrictive activity. OBJECTIVE: To determine the optimal concentration and dose regimen of topical BT gel for the treatment of erythema of rosacea and to evaluate its efficacy and safety. METHODS: In study A, 122 subjects were randomized to receive a single application of BT 0·07%, 0·18%, 0·5% or vehicle. In study B (4-week treatment and 4-week follow-up), 269 subjects were randomized to receive BT 0·5% once daily, BT 0·18% once daily, vehicle once daily, BT 0·18% twice daily or vehicle twice daily. Evaluations included Clinician's Erythema Assessment (CEA), Patient's Self-Assessment (PSA), Chroma Meter measurements and adverse events. RESULTS: In study A, a single application of topical BT gel reduced facial erythema in a dose-dependent fashion. A significant difference between BT 0·5% and vehicle in Chroma Meter redness value was observed from 30min to 12h after application. In study B, BT 0·5% once daily had a statistically superior success profile (defined as a two-grade improvement on both CEA and PSA over 12h) compared with vehicle once daily on days 1, 15 and 29 (all P<0·001). No tachyphylaxis, rebound of erythema or aggravation of other disease signs (telangiectasia, inflammatory lesions) was observed. All regimens were safe and well tolerated with similarly low incidence of adverse events. CONCLUSIONS: Once-daily BT gel 0·5% is well tolerated and provides significantly greater efficacy than vehicle gel for the treatment of moderate to severe erythema of rosacea.

A longitudinal study of predictors of research-defined carpal tunnel syndrome in industrial workers: findings at 17 years.

In 1984, we initiated a prospective study of factors associated with research-defined carpal tunnel syndrome (CTS) in 471 industrial workers. Medical history, lifestyle factors and job tasks were assessed by questionnaire and CTS case status was based on both symptoms and electrophysiologic findings. Participants were re-examined in 1989, 1994 to 1995 and 2001 to 2002. This study reports both baseline and aggregated risk factors associated with increased risk of CTS by 2001 to 2002 for 166 participants successfully re-examined after 17 years. In analyses of baseline risk factors, fewer repetitive tasks at work, female gender and greater relative weight were associated with any occurrence of CTS during follow-up. In analyses of aggregate risk factor scores through 1994 to 1995, only greater relative weight and female gender were associated with CTS in 2001 to 2002. Although obesity and gender are consistent predictors of CTS, workplace demands appear to bear an uncertain relationship to CTS. These findings are also discussed in relation to the possible differences between research-defined CTS and medically referred CTS.

Intermediate and long-term outcomes following simple decompression of the ulnar nerve at the elbow.

INTRODUCTION: There is currently little consensus regarding the appropriate surgical approach to treatment of cubital tunnel syndrome (CubTS), and few studies have reported long-term follow-up of patients who have received surgical treatment for ulnar nerve compression at the elbow. METHOD: Seventy-four patients with a total of 102 cases of CubTS treated with simple decompression of the ulnar nerve were examined 1.0-12.4 years postoperatively. Ulnar nerve conduction studies (slowest conducting 5 cm segment of ulnar nerve motor fibers measured at the elbow) were performed both pre- and postoperatively. The primary clinical outcome was percentage relief of symptoms, divided into "excellent" outcome group or less (> or = 90% improvement or < 90% improvement). RESULTS: Ulnar nerve conduction improved pre- to postoperatively, but clinical improvement was not related to changes in velocity. Women reported greater clinical improvement than men, and weight gain in men (but not women) predicted less improvement. Relief of cubital tunnel symptoms was greatest for those arms receiving carpal tunnel release surgery simultaneous or subsequent to cubital tunnel release. DISCUSSION: Simple decompression may offer excellent intermediate and long-term relief of symptoms associated with CubTS. Although improvement in ulnar motor nerve conduction velocity occurs following treatment of CubTS, it may not be a consistent marker of perceived symptom relief. Finally, these findings suggest that less complete relief of symptoms following ulnar nerve decompression may be related to unrecognized carpal tunnel syndrome or weight gain.

Number of non-diabetic drugs: a simple comorbidity indicator for diabetes?

INTRODUCTION: The number of non-diabetic drugs, taken by a patient with diabetes at any one point in time, has been validated in previous studies as a comorbidity indicator. AIM: The aim of the paper is to examine the relationship between this comorbidity indicator and health status in people with Type 2 diabetes. METHOD: The analysis presented is from a prospective cohort study of people with Type 2 diabetes before and after commencing insulin therapy, with simultaneous collection of health status, clinical and other comparative data. RESULTS: Of the 48 people for whom both health status and drug data were available, 26 (54%) were taking at least one non-diabetic drug and 16 (33%) were taking 3 or more non-diabetic drugs, at the baseline assessment. There were no significant relationships between the number of non-diabetic drugs taken, and age, duration of diabetes or baseline HbA1c measurements. However, there were statistically significant relationships between the number of non-diabetic drugs and health status, in terms of depression and physical function. CONCLUSION: Drug data are routinely recorded in primary care and therefore the number of non-diabetic drugs is a potentially widely available indicator. This indicator could be a useful, simple addition to datasets that not only proxies comorbidity but also relates to patients' physical function and depression status.

Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation.

We investigated the role of Ras in vascular endothelial growth factor (VEGF)-mediated signal transduction and the promotion of angiogenic changes primary endothelial cells. We find that VEGF potently induces Ras activation and that this step is essential for the stimulation by VEGF of several cellular changes associated with angiogenesis, including proliferation, migration, and branching morphogenesis in three-dimensional culture. Inhibition of Ras signaling induced subtle changes in the actin architecture but had no effect on the phosphatidylinositol 3-kinase (PI3K) or p38 signaling pathways. In contrast, activation of ERK was largely dependent on Ras. Although inhibiting ERK activity completely suppressed cell proliferation and partially blocked in vitro differentiation, neither ERK nor PI3K activity was required for VEGF-induced migration. These data provide the first direct demonstration that inhibition of Ras signal transduction is anti-angiogenic. Interestingly, VEGF signal transduction bifurcates both upstream and downstream of Ras, with different Ras-dependent signals controlling endothelial cell proliferation and migration, essential components of the angiogenic response.

Effects of an aerobic exercise program on median nerve conduction and symptoms associated with carpal tunnel syndrome.

Carpal tunnel syndrome is associated with greater body mass index and less physical activity. To determine the effect of aerobic exercise on median nerve conduction and symptoms suggestive of carpal tunnel syndrome, 30 symptomatic volunteers (30 to 64 years old) with abnormal median nerve conduction studies participated in a 10-month program of supervised aerobic exercise. Changes in percentage of body fat, body mass index, peak oxygen consumption, 14-cm median sensory latency, and hand/wrist symptoms were assessed. A decrease in 14-cm sensory median latency correlated with a decrease in percentage of body fat (R = 0.52, P = 0.004) and was predicted by an increase in peak oxygen utilization (partial R = 0.52, P = 0.005) and a decrease in body mass index (partial R = 0.47, P = 0.014). There was also a tendency for a set of symptoms sometimes associated with carpal tunnel syndrome (pain, tightness, and clumsiness) to be relieved by the exercise program. These results suggest that an aerobic exercise program can be beneficial to median nerve function and may be associated with a reduction in hand symptoms.

Insulin-like growth factors (IGF-I and IGF-II) inhibit C2 skeletal myoblast differentiation and enhance TNF alpha-induced apoptosis.

IGF-I and IGF-II are thought to be unique in their ability to promote muscle cell differentiation. Murine C2 myoblasts differentiate when placed into low serum media (LSM), accompanied by increased IGF-II and IGF binding protein-5 (IGFBP-5) production. Addition of 20 ng/ml TNF alpha on transfer into LSM blocked differentiation, IGF-II and IGFBP-5 secretion and induced apoptosis. We, therefore, wished to assess whether IGFs could protect against the effects of TNF alpha. Neither inhibition of differentiation or induction of apoptosis was rescued by co-incubation with IGF-I or IGF-II. A lower dose of TNF alpha (1 ng/ml) while not inducing apoptosis still inhibited myoblast differentiation by 56% +/- 12, (P < 0.001), indicating that induction of apoptosis is not the sole mechanism by which TNF alpha inhibits myoblast differentiation. Addition of IGF-I or IGF-II alone reduced differentiation by 49% +/- 15 and 33% +/- 20, respectively, (P < 0.001), although neither induced apoptosis. For muscle cells to differentiate, they must arrest in G0. We established that addition of IGF-I, IGF-II or TNF alpha to the myoblasts promoted proliferation. The myoblasts could not exit the cell cycle as efficiently as controls and differentiation was thus reduced. Unexpectedly, co-incubation of IGF-I or IGF-II with 1 ng/ml TNF alpha enhanced the inhibition of differentiation and induced apoptosis. In the absence of apoptosis we show an association between IGF-induced inhibition of differentiation and increased IGFBP-5 secretion. These results indicate that the effects of the IGFs on muscle may depend on the cytokine environment. In the absence of TNF alpha, the IGFs delay differentiation and promote myoblast proliferation whereas in the presence of TNF alpha the IGFs induce apoptosis.

Pigmented purpuric eruptions of childhood: a series of cases and review of literature.

Pigmented purpuric eruptions comprise a group of benign dermatoses that are characterized clinically by pinpoint petechiae and purpura on a hyperpigmented base and histologically by capillaritis. The etiology of this group of disorders is unknown, although aberrant cell-mediated immunity has been proposed. Pigmented purpuric eruptions are well characterized in the pediatric population. In this case series we present three children with these disorders and review the clinical subtypes of pigmented purpuric eruptions that have been described in the literature.

Neurologic variant of epidermal nevus syndrome with a facial lipoma.

A 1-year-old girl presented for evaluation of a linear plaque on her forehead. She was born at 36 weeks' gestation following an uncomplicated pregnancy and delivery. At birth, she was noted to have an enlarged right cheek. She had no seizure history, but developed grand mal seizures 1 year later. On examination, she had a yellow plaque on her forehead which extended onto her nose. Under her right jaw, extending onto her anterior neck, there was a café-au-lait macule within which there was a yellow plaque which followed the lines of Blaschko. Her right cheek was enlarged and was erythematous (Fig. 1). Magnetic resonance imaging (MRI) of her face showed a mass in the right cheek deep to the subcutaneous fat tissue layer. The signal from the mass was identical to that from the fat, indicating that the mass represented a lipoma. This was later excised surgically and was histologically a lipoma. MRI of the brain demonstrated enlargement of the right lateral ventricle in addition to enlargement of the right cerebral hemisphere. There was also evidence of abnormal gyral architecture. Computerized tomography (CT) three-dimensional reconstruction of the skull demonstrated overgrowth of the right maxilla, right mandible, and right orbit (Fig. 2).

The impact of different response alternatives on responders' reporting of health-related behaviour in a postal survey.

Previous experimental research in other topic areas has shown that the choice of response alternatives can influence respondents' reporting of the frequency of vaguely defined events and that the set of response alternatives is treated as information in the interpretation of the question. The aim of this study was to examine whether such affects would occur in the context of respondents reporting of health-related events using high and medium frequency closed format response categories, which might be used interchangeably by researchers. The study consisted of a postal survey of n = 518 patients aged > or = 18 years randomly selected from the patient list of a diabetes centre and who were equally and randomly allocated to one of three conditions (Condition A: high frequency response alternatives/horizontal orientation; condition B: medium frequency response alternatives/horizontal orientations; condition C: high frequency response alternatives/vertical orientation). Testing for the effect of response alternatives for the combined responses of five vaguely defined questions between conditions A and B was chi 2 = 5.5, p = 0.019, for the difference in proportions, indicating that overall, those respondents presented with response alternatives discriminating at medium frequency, reported significantly fewer target events than those presented with high frequency response alternatives. Testing for the effect of orientation of the combined question responses between conditions A and C, differences in proportions between conditions, did not reach statistical significance (p > 0.05). Findings from this and previous studies indicate that response alternatives provide information on the interpretation of vaguely defined questionnaire items and that their choice should not be left to intuition alone when designing questionnaire items.

Adaptation of the Diabetes Health Profile (DHP-1) for use with patients with Type 2 diabetes mellitus: psychometric evaluation and cross-cultural comparison.

AIMS: To adapt the Diabetes Health Profile (DHP-1) for use with English speaking patients with Type 2 diabetes mellitus and to evaluate the psychometric properties of the adapted measure in a UK and Danish sample of insulin, tablet and diet-treated patients with Type 2 diabetes. METHODS: Following linguistic adaptation using the forward-backward translation procedure, the 32-item DHP-1 was sent to 650 and 800 consecutively selected UK and Danish patients with Type 2 diabetes. Construct validity was assessed using principal axis factoring. Factor stability was assessed across language groups using the coefficient of congruence. Reliability was evaluated using Cronbach's alpha and multi-trait analysis, including item convergent/discriminant validity. Subscale discriminant validity was assessed through known groups with one-way ANOVA and post hoc Scheffe tests for multiple comparisons. RESULTS: Eighteen items (56.25%) were retained following initial item analysis. A three-factor solution accounting for 45.6% and 40.3% of the total explained variance was identified in the UK and Danish samples, respectively. Factors were interpreted as psychological distress (PD), barriers to activity (BA) and disinhibited eating (DE). Factor congruence between language groups ranged from 0.98 to 0.99 and Cronbach's alpha ranged between 0.70 and 0.88. Item scaling success for both language versions was 88.9%. BA scores discriminated between treatment groups in both language groups (F = 24.24, P < 0.001; F = 7.68, P < 0.001) and PD scores in the UK sample (F = 20.97, P < 0.001). CONCLUSIONS: The DHP-18 developed for use with patients with Type 2 diabetes has been shown to have satisfactory internal reliability and validity and measurement equivalence across language groups.

Acute generalized exanthematous pustulosis (AGEP), an uncommon condition in children: case report and review of the literature.

Acute generalized exanthematous pustulosis (AGEP) is characterized by acute onset of a widespread pustular eruption in association with fever. It is usually seen as a medication reaction. We describe a 17-month-old boy with AGEP secondary to exposure to amoxicillin. This is an uncommon condition in children.