Search Results (24)

Background: Treatment compliant with the Global Initiative for Asthma (GINA) can promote more effective disease control. Single-inhaler triple therapy (SITT) is one method that is used to optimize therapy in this context, but TRIPLE therapy is still employed by physicians to a limited extent. Objective: This study aimed to describe the factors influencing challenges in optimizing asthma therapy. Methods: A 19-question survey, created via the CATI system, was distributed among pulmonologists, allergologists, general practitioners, and internal medicine specialists in Poland, Greece, Sweden, Slovenia, and Austria. Results: Statistically significant percentage differences in the use of TRIPLE therapy in the context of asthma management were observed among countries as well as between pulmonologists, allergists, and other specialists. Overuse of oral corticosteroids (OCSs) to treat nonsevere and severe asthma in the absence of an approach that focuses on optimizing inhalation therapy among asthma patients receiving TRIPLE therapy was observed in different countries as well as among physicians with different specialties. Twenty elements associated with the challenges involved in diagnosing and managing difficult-to-treat and severe asthma were identified. Six clinical categories for the optimization of asthma therapy via SITT were highlighted. The degree of therapeutic underestimation observed among severe asthma patients was assessed by comparing actual treatment with the recommendations of the GINA 2023 guidelines. Conclusions: Physicians of various specialties in Europe are subject to therapeutic inertia in terms of their compliance with the GINA 2023 guidelines. Full article

The present Perspective analyzes the remarkable evolution of the Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory of Alzheimer’s disease (AD) since its inception a few years ago, as reflected in the diminishing role of amyloid-beta (Aβ) in the disease. In the initial iteration of the ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. The neuronal ISR, in turn, activates the AβPP-independent production of its C99 fragment that is processed into iAβ, which drives the disease. The second iteration of the ACH2.0 stemmed from the realization that AD is, in fact, a disease of the sustained neuronal ISR. It introduced two categories of AD—conventional and unconventional—differing mainly in the manner of their causation. The former is caused by the neuronal ISR triggered by AβPP-derived iAβ, whereas in the latter, the neuronal ISR is elicited by stressors distinct from AβPP-derived iAβ and arising from brain trauma, viral and bacterial infections, and various types of inflammation. Moreover, conventional AD always contains an unconventional component, and in both forms, the disease is driven by iAβ generated independently of AβPP. In its third, the current, iteration, the ACH2.0 posits that proteolytic production of Aβ is suppressed in AD-affected neurons and that the disease is driven by C99 generated independently of AβPP. Suppression of Aβ production in AD seems an oxymoron: Aβ is equated with AD, and the later is inconceivable without the former in an ingrained Amyloid Cascade Hypothesis (ACH)-based notion. But suppression of Aβ production in AD-affected neurons is where the logic leads, and to follow it we only need to overcome the inertia of the preexisting assumptions. Moreover, not only is the generation of Aβ suppressed, so is the production of all components of the AβPP proteolytic pathway. This assertion is not a quantum leap (unless overcoming the inertia counts as such): the global cellular protein synthesis is severely suppressed under the neuronal ISR conditions, and there is no reason for constituents of the AβPP proteolytic pathway to be exempted, and they, apparently, are not, as indicated by the empirical data. In contrast, tau protein translation persists in AD-affected neurons under ISR conditions because the human tau mRNA contains an internal ribosomal entry site in its 5′UTR. In current mouse models, iAβ derived from AβPP expressed exogenously from human transgenes elicits the neuronal ISR and thus suppresses its own production. Its levels cannot principally reach AD pathology-causing levels regardless of the number of transgenes or the types of FAD mutations that they (or additional transgenes) carry. Since the AβPP-independent C99 production pathway is inoperative in mice, the current transgenic models have no potential for developing the full spectrum of AD pathology. What they display are only effects of the AβPP-derived iAβ-elicited neuronal ISR. The paper describes strategies to construct adequate transgenic AD models. It also details the utilization of human neuronal cells as the only adequate model system currently available for conventional and unconventional AD. The final alteration of the ACH2.0, introduced in the present Perspective, is that AβPP, which supports neuronal functionality and viability, is, after all, potentially produced in AD-affected neurons, albeit not conventionally but in an ISR-driven and -compatible process. Thus, the present narrative begins with the “omnipotent” Aβ capable of both triggering and driving the disease and ends up with this peptide largely dislodged from its pedestal and retaining its central role in triggering the disease in only one, although prevalent (conventional), category of AD (and driving it in none). Among interesting inferences of the present Perspective is the determination that “sporadic AD” is not sporadic at all (“non-familial” would be a much better designation). The term has fatalistic connotations, implying that the disease can strike at random. This is patently not the case: The conventional disease affects a distinct subpopulation, and the basis for unconventional AD is well understood. Another conclusion is that, unless prevented, the occurrence of conventional AD is inevitable given a sufficiently long lifespan. This Perspective also defines therapeutic directions not to be taken as well as auspicious ways forward. The former category includes ACH-based drugs (those interfering with the proteolytic production of Aβ and/or depleting extracellular Aβ). They are legitimate (albeit inefficient) preventive agents for conventional AD. There is, however, a proverbial snowball’s chance in hell of them being effective in symptomatic AD, lecanemab, donanemab, and any other “…mab” or “…stat” notwithstanding. They comprise Aβ-specific antibodies, inhibitors of beta- and gamma-secretase, and modulators of the latter. In the latter category, among ways to go are the following: (1) Depletion of iAβ, which, if sufficiently “deep”, opens up a tantalizing possibility of once-in-a-lifetime preventive transient treatment for conventional AD and aging-associated cognitive decline, AACD. (2) Composite therapy comprising the degradation of C99/iAβ and concurrent inhibition of the neuronal ISR. A single transient treatment could be sufficient to arrest the progression of conventional AD and prevent its recurrence for life. Multiple recurrent treatments would achieve the same outcome in unconventional AD. Alternatively, the sustained reduction/removal of unconventional neuronal ISR-eliciting stressors through the elimination of their source would convert unconventional AD into conventional one, preventable/treatable by a single transient administration of the composite C99/iAβ depletion/ISR suppression therapy. Efficient and suitable ISR inhibitors are available, and it is explicitly clear where to look for C99/iAβ-specific targeted degradation agents—activators of BACE1 and, especially, BACE2. Directly acting C99/iAβ-specific degradation agents such as proteolysis-targeting chimeras (PROTACs) and molecular-glue degraders (MGDs) are also viable options. (3) A circumscribed shift (either upstream or downstream) of the position of transcription start site (TSS) of the human AβPP gene, or, alternatively, a gene editing-mediated excision or replacement of a small, defined segment of its portion encoding 5′-untranslated region of AβPP mRNA; targeting AβPP RNA with anti-antisense oligonucleotides is another possibility. If properly executed, these RNA-based strategies would not interfere with the protein-coding potential of AβPP mRNA, and each would be capable of both preventing and stopping the AβPP-independent generation of C99 and thus of either preventing AD or arresting the progression of the disease in its conventional and unconventional forms. The paper is interspersed with “validation” sections: every conceptually significant notion is either validated by the existing data or an experimental procedure validating it is proposed. Full article

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, underscoring the importance of effective primary prevention strategies. Current total cardiovascular disease (CVD) risk assessment tools, such as the Systematic Coronary Risk Evaluation 2 (SCORE2) in Europe and the Pooled cohort equations (PCEs) and Predicting Risk of CVD EVENTs (PREVENT) in the USA, aim to identify individuals at high CVD risk and guide clinical decision-making in the primary prevention setting. Statin therapy reduces cardiovascular events and is recommended as the first step for individuals with estimated CVD risk above specific thresholds. Moreover, the presence of risk modifiers, as well as the detection of asymptomatic atherosclerosis, reclassifies low-moderate CVD risk individuals into higher risk categories, contributing to tailored therapeutic decisions in primary prevention. However, differences in the performance of the available CVD risk assessment tools, the recommended thresholds for intervention, and the treatment targets by scientific societies introduce considerable inconsistency to the statin therapy practices. In addition, physicians’ inertia and poor patients’ adherence contribute to inadequate dyslipidemia control rates. This narrative review examines the available evidence on the current most used CVD risk assessment tools and the respective lipid-lowering recommendations, and highlights the role of targeted screening for asymptomatic atherosclerosis in terms of individualized therapy for primary prevention. Full article

Background and Objectives: Elevated blood sugar poses an increasingly significant challenge to healthcare systems worldwide. We aimed to assess the efficacy of the SGLT-2i class in achieving metabolic control in patients with T2DM within a real-world standard-of-care regimen. Material and Methods: A prospective analysis was conducted over 6 months including individuals receiving care in an outpatient department, with baseline assessments and follow-ups at 3 and 6 months. Results: A total of 280 patients were assessed, with a mean age of 63.69 ± 9.16, 53.9% of which were males, with a mean DM duration of 9.06 ± 5.64 years, and a DM duration varying from 6 months to 24 years. Discussion: Real-world evidence bridges the gap between guidelines and practice. It emphasizes the need to overcome clinical inertia in order to optimize patient outcomes and contributes to the body of evidence supporting the efficacy of fixed-dose SGLT-2i combinations in managing T2DM and associated comorbidities. Conclusions: We demonstrate the significant clinical and therapeutic impact of SGLT-2i in T2DM patients in a real-world setting. This class of medication not only positively influences glycemic and weight control but also reduces CV risk factors and visceral adiposity. Full article

Background/Objectives: This study assessed the proportion of secondary cardiovascular prevention patients who achieved low-density lipoprotein (LDL) cholesterol targets as per the 2019 ESC/EAS Dyslipidemia Guidelines. We also evaluated whether lipid-lowering therapies (LLTs) were adjusted in patients not meeting targets and analyzed the likelihood of these modifications achieving recommended levels. Methods: A multicenter, cross-sectional observational study retrospectively reviewed medical records of 1909 outpatients in 9 Italian cardiac rehabilitation/secondary prevention clinics from January 2023 to June 2024. Inclusion criteria included prior atherosclerotic cardiovascular disease (ASCVD) and recent LDL-cholesterol levels. Data included demographics, ASCVD presentation, lipid profiles, and LLTs. Patients at very high risk had LDL targets of ≤55 mg/dL, or ≤40 mg/dL for recurrent events within 2 years. Clinicians’ approaches to LLT modification in patients not at target were recorded, with LLT efficacy estimated based on percentage distance from LDL-cholesterol targets. Results: Of the 1909 patients, 41.3% met the LDL-cholesterol target. Predictors of achieving targets included male gender, cardiac rehabilitation, recent acute coronary syndrome, diabetes, and triple therapy (statin + ezetimibe + PCSK9 inhibitors). Conversely, a target of ≤40 mg/dL, lack of therapy, and monotherapy were negative predictors. Among 1074 patients not at target, LLT modifications were proposed for 48.6%. Predictors of LLT modification included recent ASCVD events, cardiac rehabilitation, and greater percentage distance from the LDL target, while advanced age and an LDL target of ≤40 mg/dL were negative predictors. However, only 42.3% of modified therapies were predicted to be effective in reaching LDL targets. Conclusions: Despite 2019 ESC/EAS guidelines, a significant proportion of high-risk patients did not achieve LDL targets, and proposed LLT modifications were often insufficient. More intensive LLT regimens are needed to improve outcomes in this population. Full article

Bridged polysilsesquioxanes (BPSs) are emerging biomaterials composed of synergistic inorganic and organic components. These materials have been investigated as ideal carriers for therapeutic and diagnostic systems for their favorable properties, including excellent biocompatibility, physiological inertia, tunable size and morphology, and their extensive design flexibility of functional organic groups to satisfy diverse application requirements. Stimuli-responsive BPSs can be activated by both endogenous and exogenous stimuli, offering a precise, safe, and effective platform for the controlled release of various targeted therapeutics. This review aims to provide a comprehensive overview of stimuli-responsive BPSs, focusing on their synthetic strategies, biocompatibility, and biodegradability, while critically assessing their capabilities for controlled release in response to specific stimuli. Furthermore, practical suggestions and future perspectives for the design and development of BPSs are presented. This review highlights the significant role of stimuli-responsive BPSs in advancing biomedical research. Full article

Seasonal variations in glycaemic patterns in children and young adults affected by type 1 diabetes are currently poorly studied. However, the spread of Flash Glucose Monitoring (FGM) and continuous glucose monitoring (CGM) systems and of dedicated platforms for the synchronization and conservation of CGM reports allows an efficient approach to the comprehension of these phenomena. Moreover, the impact that environmental parameters may have on glycaemic control takes on clinical relevance, implying a need to properly educate patients and their families. In this context, it can be investigated how blood glucose patterns in diabetic patients may have a link to outdoor temperatures. Therefore, in this study, the relationship between outdoor temperatures and glucose levels in diabetic patients, aged between 4 and 21 years old, has been analysed. For a one-year period (Autumn 2022–Summer 2023), seasonal variations in their CGM metrics (i.e., time in range (TIR), Time Above Range (TAR), Time Below Range (TBR), and coefficient of variation (CV)) were analysed with respect to atmospheric temperature. The results highlight a negative correlation between glucose in diabetic patients and temperature patterns (R value computed considering data for the entire year; Ry = −0.49), behaviour which is strongly confirmed by the analysis focused on the July 2023 heatwave (R = −0.67), which shows that during heatwave events, the anticorrelation is accentuated. The diurnal analysis shows how glucose levels fluctuate throughout the day, potentially correlating with atmospheric diurnal temperature changes in addition to the standard trend. Data captured during the July 2023 heatwave (17–21 July 2023) highlight pronounced deviations from the long-term average, signalling the rapid effects of extreme temperatures on glucose regulation. Our findings underscore the need to integrate meteorological parameters into diabetes management and clinical trial designs. These results suggest that structured diabetes self-management education of patients and their families should include adequate warnings about the effects of atmospheric temperature variations on the risk of hypoglycaemia and about the negative effects of excessive therapeutic inertia in the adjustment of insulin doses. Full article

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics, glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2-in). Despite new guidelines, clinical inertia, which can be caused by physicians, patients or the healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient’s overall situation in decision-making. We looked for the possible reasons for clinical inertia and the poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiatives in diabetes aim to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings. Full article

Background: International guidelines for diabetes care emphasize the urgency of promptly achieving and sustaining adequate glycemic control to reduce the occurrence of micro/macrovascular complications in patients with type 2 diabetes mellitus (T2DM). However, data from the Italian Association of Medical Diabetologists (AMD) Annals reveal that only 47% of T2DM patients reach appropriate glycemic targets, with approximately 30% relying on insulin therapy, either solely or in combination. This artificial intelligence analysis seeks to assess the potential impact of timely insulin initiation in all eligible patients via a “what-if” scenario simulation, leveraging real-world data. Methods: This retrospective cohort study utilized the AMD Annals database, comprising 1,186,247 T2DM patients from 2005 to 2019. Employing the Logic Learning Machine (LLM), we simulated timely insulin use for all eligible patients, estimating its effect on glycemic control after 12 months within a cohort of 85,239 patients. Of these, 20,015 were employed for the machine learning phase and 65,224 for simulation. Results: Within the simulated scenario, the introduction of appropriate insulin therapy led to a noteworthy projected 17% increase in patients meeting the metabolic target after 12 months from therapy initiation within the cohort of 65,224 individuals. The LLM’s projection envisages 32,851 potential patients achieving the target (hemoglobin glycated < 7.5%) after 12 months, compared to 21,453 patients observed in real-world cases. The receiver operating characteristic (ROC) curve analysis for this model demonstrated modest performance, with an area under the curve (AUC) value of 70.4%. Conclusions: This study reaffirms the significance of combatting therapeutic inertia in managing T2DM patients. Early insulinization, when clinically appropriate, markedly enhances patients’ metabolic goals at the 12-month follow-up. Full article

Reducing low-density lipoprotein cholesterol (LDL-C) levels is crucial to the prevention of atherosclerotic cardiovascular disease (ASCVD). However, many patients, especially those at very high ASCVD risk or with familial hypercholesterolemia (FH), do not achieve target LDL-C levels with statin monotherapy. The underutilization of novel lipid-lowering therapies (LLT) globally may be due to cost concerns or therapeutic inertia. Emerging approaches have the potential to lower LDL-C and reduce ASCVD risk further, in addition to offering alternatives for statin-intolerant patients. Shifting the treatment paradigm towards initial combination therapy and utilizing novel LLT strategies can complement existing treatments. This review discusses innovative approaches including combination therapies involving statins and agents like ezetimibe, bempedoic acid, cholesterol ester transfer protein (CETP) inhibitors as well as strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and angiopoietin-like protein 3 (ANGPTL3) inhibition. Advances in nucleic acid-based therapies and gene editing are innovative approaches that will improve patient compliance and adherence. These strategies demonstrate significant LDL-C reductions and improved cardiovascular outcomes, offering potential for optimal LDL-C control and reduced ASCVD risk. By addressing the limitations of statin monotherapy, these approaches provide new management options for elevated LDL-C levels. Full article

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological “coldness”, however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This “radiovaccination” effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC. Full article

Few studies have investigated the effect of a monosaturated diet high in ω-9 on osteoporosis. We hypothesized that omega-9 (ω-9) protects ovariectomized (OVX) mice from a decline in bone microarchitecture, tissue loss, and mechanical strength, thereby serving as a modifiable dietary intervention against osteoporotic deterioration. Female C57BL/6J mice were assigned to sham-ovariectomy, ovariectomy, or ovariectomy + estradiol treatment prior to switching their feed to a diet high in ω-9 for 12 weeks. Tibiae were evaluated using DMA, 3-point-bending, histomorphometry, and microCT. A significant decrease in lean mass (p = 0.05), tibial area (p = 0.009), and cross-sectional moment of inertia (p = 0.028) was measured in OVX mice compared to the control. A trend was seen where OVX bone displayed increased elastic modulus, ductility, storage modulus, and loss modulus, suggesting the ω-9 diet paradoxically increased both stiffness and viscosity. This implies beneficial alterations on the macro-structural, and micro-tissue level in OVX bone, potentially decreasing the fracture risk. Supporting this, no significant differences in ultimate, fracture, and yield stresses were measured. A diet high in ω-9 did not prevent microarchitectural deterioration, nevertheless, healthy tibial strength and resistance to fracture was maintained via mechanisms independent of bone structure/shape. Further investigation of ω-9 as a therapeutic in osteoporosis is warranted. Full article

This review seeks to establish, through the recent available literature, the prevalence of therapeutic intensification delay and its sequences in poorly controlled Type 2 Diabetes Mellitus (T2DM) patients. The strategy identified studies exploring the clinical inertia and its associated factors in the treatment of patients with T2DM. A total of 25 studies meeting the pre-established quality criteria were included in this review. These studies were conducted between 2004 and 2021 and represented 575,067 patients diagnosed with T2DM. Trusted electronic bibliographic databases, including Medline, Embase, and the Cochrane Central Register of Controlled Trials, were used to collect studies by utilizing a comprehensive set of search terms to identify Medical Subject Headings (MeSH) terms. Most o the studies included in this review showed clinical inertia rates over 50% of T2DM patients. In the USA, clinical inertia ranged from 35.4% to 85.8%. In the UK, clinical inertia ranged from 22.1% to 69.1%. In Spain, clinical inertia ranged from 18.1% to 60%. In Canada, Brazil, and Thailand, clinical inertia was reported as 65.8%, 68%, and 68.4%, respectively. The highest clinical inertia was reported in the USA (85.8%). A significant number of patients with T2DM suffered from poor glycemic control for quite a long time before treatment intensification with oral antidiabetic drugs (OADs) or insulin. Barriers to treatment intensification exist at the provider, patient, and system levels. There are deficiencies pointed out by this review at specialized centers in terms of clinical inertia in the management of T2DM including in developed countries. This review shows that the earlier intensification in the T2DM treatment is appropriate to address issues around therapeutic inertia. Full article

A substantial proportion of patients with heart failure (HF) receive suboptimal guideline-recommended therapy. We aimed to identify the factors leading to suboptimal drug prescription in HF and according to HF phenotypes. This retrospective, single-centre observational cohort study included 702 patients admitted for worsening HF (HF with a reduced ejection fraction [HFrEF], n = 198; HF with a mildly reduced EF [HFmrEF], n = 122; and HF with a preserved EF [HFpEF], n = 382). A score based on the prescription and dose percentage of ACEi/ARBs, β-blockers, and MRAs at discharge was calculated (a total score ranging from zero to six). Approximately 70% of patients received ACEi/ARBs/ARNi, 80% of patients received β-blockers, and 20% received MRAs. The mean HF drug dose was approximately 50% of the recommended dose, irrespective of the HF phenotype. Ischaemic heart disease was associated with a higher prescription score (ranging from 0.4 to 1) compared to no history of ischaemic heart disease, irrespective of the left ventricular EF (LVEF) level. A lower prescription score was associated with older age and male sex in HFrEF and diabetes in HFmrEF. The overall ability of the models to predict the optimal drug dose, including key HF variables (including natriuretic peptides at admission), was poor (R² < 0.25). A higher prescription score was associated with a lower risk of re-hospitalization and death (HR: 0.75 (0.57–0.97), p = 0.03), irrespective of phenotype (p-interaction = 0.41). Despite very different HF management guidelines according to LVEF, the prescription pattern of HF drugs is poorly related to LVEF and clinical characteristics, thus suggesting that physician-driven factors may be involved in the setting of therapeutic inertia. It may also be related to drug intolerance or clinical stability that is not predicted by the patients’ profiles. Full article

Saudi Arabia is a country with high prevalence of diabetes, uncontrolled diabetes, and diabetes-related complications. Poor glycemic control is multifactorial and could be explained in part by physician and patient reluctance toward insulin or insulin inertia. This study aimed to address physician barriers toward insulin therapy in primary care settings. It included 288 physicians from 168 primary healthcare centers (PHC) in the Jazan region of Saudi Arabia. Participants responded to questionnaire investigating physicians’ attitude and barriers to insulin initiation and intensification in PHCs. In physician opinion, the most common barriers among their patients were fear of injection, lack of patient education, fear of hypoglycemia, and difficult administration. Physicians were reluctant to initiate insulin for T2D patients mostly due to patient non-adherence to blood sugar measurement, non-adherence to appointment or treatment, elderly patients, or due to patient refusal. Physicians’ fear of hypoglycemia, lack of staff for patient education, and lack of updated knowledge were the primary clinician-related barriers. Exaggerated fears of insulin side effects, patient non-adherence, limited staff for patient’s education, patient refusal, and inadequate consultation time were the main barriers to insulin acceptance and prescription. Full article