Advances and counterpoints in type 2 diabetes. What is ready for translation into real-world practice, ahead of the guidelines.

This review seeks to address major gaps and delays between our rapidly evolving body of knowledge on type 2 diabetes and its translation into real-world practice. Through updated and improved best practices informed by recent evidence and described herein, we stand to better attain A1c targets, help preserve beta cell integrity and moderate glycemic variability, minimize treatment-emergent hypoglycemia, circumvent prescribing to "treatment failure," and prevent long-term complications. The first topic addressed in this review concerns updates in the 2023 and 2024 diabetes treatment guidelines for which further elaboration can help facilitate integration into routine care. The second concerns advances in diabetes research that have not yet found their way into guidelines, though they are endorsed by strong evidence and are ready for real-world use in appropriate patients. The final theme addresses lingering misconceptions about the underpinnings of type 2 diabetes-fundamental fallacies that continue to be asserted in the textbooks and continuing medical education upon which physicians build their approaches. A corrected and up-to-date understanding of the disease state is essential for practitioners to both conceptually and translationally manage initial onset through late-stage type 2 diabetes.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Frailty identification and management among Brazilian healthcare professionals: a survey.

BACKGROUND: National and international guidelines on frailty assessment and management recommend frailty screening in older people. This study aimed to determine how Brazilian healthcare professionals (HCPs) identify and manage frailty in practice. METHODS: An anonymous online survey on the assessment and management of frailty was circulated virtually through HCPs across Brazil. RESULTS: Most of the respondants used non-specific criteria such as gait speed (45%), handgrip strength (37.6%), and comprehensive geriatric assessment (33.2%). The use of frailty-specific criteria was lower than 50%. The most frequently used criteria were the Frailty Index (19.1%), Frailty Phenotype (13.2%), and FRAIL (12.5%). Only 43.5% felt confident, and 40% had a plan to manage frailty. In the multivariate-adjusted models, training was the most crucial factor associated with assessing frailty, confidence, and having a management plan (p < 0.001 for all). Those with fewer years of experience were more likely to evaluate frailty (p = 0.009). Being a doctor increased the chance of using a specific tool; the opposite was true for dietitians (p = 0.03). Those who assisted more older people had a higher likelihood of having a plan (p = 0.011). CONCLUSION: Frailty assessment was heterogeneous among healthcare professions groups, predominantly using non-specific criteria. Training contributed to frailty assessment, use of specific criteria, confidence, and having a management plan. This data informs the need for standardized screening criteria and management plans for frailty, in association with increasing training at the national level for all the HCPs who assist older people.

Therapeutic Inertia and Delays in Insulin Intensification in Type 2 Diabetes: A Literature Review.

Background: Therapeutic inertia leading to delays in insulin initiation or intensification is a major contributor to lack of optimal diabetes care. This report reviews the literature summarizing data on therapeutic inertia and delays in insulin intensification in the management of type 2 diabetes. Methods: A literature search was conducted of the Allied & Complementary Medicine, BIOSIS Previews, Embase, EMCare, International Pharmaceutical Abstracts, MEDLINE, and ToxFile databases for clinical studies, observational research, and meta-analyses from 2012 to 2022 using search terms for type 2 diabetes and delay in initiating/intensifying insulin. Twenty-two studies met inclusion criteria. Results: Time until insulin initiation among patients on two to three antihyperglycemic agents was at least 5 years, and mean A1C ranged from 8.7 to 9.8%. Early insulin intensification was linked with reduced A1C by 1.4%, reduction of severe hypoglycemic events from 4 to <1 per 100 person-years, and diminution in risk of heart failure (HF) by 18%, myocardial infarction (MI) by 23%, and stroke by 28%. In contrast, delayed insulin intensification was associated with increased risk of HF (64%), MI (67%), and stroke (51%) and a higher incidence of diabetic retinopathy. In the views of both patients and providers, hypoglycemia was identified as a primary driver of therapeutic inertia; 75.5% of physicians reported that they would treat more aggressively if not for concerns about hypoglycemia. Conclusion: Long delays before insulin initiation and intensification in clinically eligible patients are largely driven by concerns over hypoglycemia. New diabetes technology that provides continuous glucose monitoring may reduce occurrences of hypoglycemia and help overcome therapeutic inertia associated with insulin initiation and intensification.

Understanding the Patient Perspective When Designing Future Rehabilitation Interventions after Hip or Knee Replacement Surgery-A Patient and Public Involvement Exercise.

Background and Objectives: Following discharge from hospital, there can be variability in the rehabilitation of patients who have undergone total hip or knee replacement surgery. We invited patients who had had hip or knee replacement surgery to take part in patient and public involvement sessions to help us understand their recovery needs and how rehabilitation services could potentially be improved to meet these needs better. Materials: Patients (n = 14) were invited to one of two patient advisory group sessions which took place in a university setting. Results: Feedback from patients highlighted the need for an inclusive, evidence-based intervention that would benefit patients experiencing all levels of pain, with differing motivations for recovery. Patients desired social support with others who have had similar surgery to reduce the burden of isolation during rehabilitation. Furthermore, patients valued the involvement of their partners and carers in their rehabilitation, to provide social support and guidance on recovery. Patients also expressed a need for consistent information and expert guidance on all aspects of their recovery. Conclusions: These findings can be used to guide the design of rehabilitation interventions following hip and knee replacement and ensure that patient perspectives inform future practice.

Experiences of self-care during the COVID-19 pandemic among individuals with rheumatoid arthritis: A qualitative study.

OBJECTIVES: This study aimed to explore the impact of the coronavirus disease 2019 (COVID-19) pandemic on self-care of individuals living with rheumatoid arthritis (RA). METHODS: Guided by a constructivist, qualitative design, we conducted one-to-one in-depth telephone interviews between March and October 2020 with participants with RA purposively sampled for maximum variation in age, sex and education, who were participating in one of two ongoing randomized-controlled trials. An inductive, reflexive thematic analysis approach was used. RESULTS: Twenty-six participants (aged 27-73 years; 23 females) in British Columbia, Canada were interviewed. We identified three themes: (1) Adapting to maintain self-care describes how participants took measures to continue self-care activities while preventing virus transmissions. While spending more time at home, some participants reported improved self-care. (2) Managing emotions describes resilience-building strategies such as keeping perspective, positive reframing and avoiding negative thoughts. Participants described both letting go and maintaining a sense of control to accommodate difficulties and emotional responses. (3) Changing communication with health professionals outlined positive experiences of remote consultations with health professionals, particularly if good relationships had been established prepandemic. CONCLUSION: The insights gained may inform clinicians and researchers on ways to support the self-care strategies of individuals with RA and other chronic illnesses during and after the COVID-19 pandemic. The findings reveal opportunities to further examine remote consultations to optimize patient engagement and care. PATIENT OR PUBLIC CONTRIBUTION: This project is jointly designed and conducted with patient partners in British Columbia, Canada. Patient partners across the United Kingdom also played in a key role in providing interpretations of themes during data analysis.

Role of Hypothermia in Adult Cardiac Surgery Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To review studies that assessed systemic hypothermia as an organ protection strategy in adults undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: Randomized controlled trials, irrespective of blinding, language, publication status, and date of publication, were identified by searching the Cochrane Central register of Controlled Trials, MEDLINE, and Embase until November 2020. Risk of bias assessment was performed according to Cochrane methodology. Treatment effects were expressed as risk ratios and 95% confidence intervals. Heterogeneity was expressed as I2. INTERVENTIONS: Systemic hypothermia. MEASUREMENTS AND MAIN RESULTS: Forty-eight trials enrolling 6,690 patients were included in the analysis. Methodologic quality of the studies included was low, mostly due to insufficient allocation concealment or blinding. Random-effects meta-analysis did not resolve uncertainty as to the risks and benefits for hypothermia versus normothermia for key primary and secondary outcomes, including mortality (1.21, 0.94 to 1.56, I2 = 0%) and brain injury (0.87, 0.67 to 1.14, I2 = 0%). Sensitivity analyses restricted to trials at low risk of important bias demonstrated higher mortality with hypothermia (1.70, 1.05 to 2.75, I2 = 0%), with little or no treatment effect on brain injury (1.01, 0.69 to 1.49, I2 = 0%). There was no interaction between cardioplegia temperature and the effects of cardiopulmonary bypass temperature on outcomes. There was insufficient evidence to assess the effects of hypothermia in noncoronary artery bypass graft surgery. CONCLUSION: The existing evidence for an organ-protective effect of hypothermia in adult cardiac surgery is of low quality and inconsistent.

Association Between Inspiratory Muscle Function and Balance Ability in Older People: A Pooled Data Analysis Before and After Inspiratory Muscle Training.

Inspiratory muscle training (IMT) improved balance ability and respiratory muscle function in healthy older adults. The current study is a retrospective analysis to explore the relationship between inspiratory muscle function, balance ability, and adaptation to IMT. All participants (total = 129; IMT = 60; age range = 65-85 years) performed inspiratory and balance assessments, including the mini-balance evaluation system test, maximal inspiratory pressure, and peak inspiratory flow tests. Baseline inspiratory muscle function was positively related to balance ability (p < .05), and IMT-induced improvements in inspiratory function (23.3% in maximal inspiratory pressure, 8.0% in peak inspiratory flow rate, 14.9% in maximal peak inspiratory power) were related to improvements in balance (10.6% in mini-balance evaluation system test), with the greatest improvements (17.0%) observed in the oldest participants (76-85 years old, p < .05). In conclusion, with or without IMT, positive associations between inspiratory function and balance ability exist, with greater improvements in inspiratory muscle function related to greater improvements in balance ability.

Blood Transfusion Threshold in Patients Receiving Extracorporeal Membrane Oxygenation Support for Cardiac and Respiratory Failure-A Systematic Review and Meta-Analysis.

OBJECTIVE: To review studies that have evaluated the effects of liberal or restrictive red cell transfusion thresholds on clinical outcomes in patients requiring extracorporeal membrane oxygenation (ECMO) support for cardiac or respiratory failure. DESIGN: A systematic review and meta-analysis. SETTING AND PARTICIPANTS: The study comprised 1,070 patients from observational studies and randomized controlled trials analyzing transfusion policies in venoarterial (VA) and venovenous (VV) ECMO adult populations. MEASUREMENTS AND MAIN RESULTS: Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials, Medline, and EMBASE until March 4, 2020, using a combination of subject headings and text words. Risk of bias assessment was performed to assess study quality according to the ROBINS-I tool and the case series studies appraisal checklist. There was high risk of bias in the studies analyzed, and none had methodologic adequacy. Three studies analyzed VA ECMO and VV ECMO patients separately. Five datasets were related exclusively or mostly to VA ECMO. Four were retrospective analyses, and one was conducted as a prospective observational study; the median transfusion threshold reported was 8 g/dL, with a mean mortality of 52%. Eight datasets were related either exclusively or mostly to VV ECMO. Six were retrospective and two were prospective observational studies; the median transfusion threshold was 8 g/dL, and the mean mortality rate was 33%. CONCLUSIONS: The present study did not resolve uncertainty as to transfusion management in ECMO, although several studies (most of them in VV ECMO) demonstrated that a restrictive threshold has acceptable outcomes in single-center cohorts.

Flash Continuous Glucose Monitoring: A Summary Review of Recent Real-World Evidence.

Optimizing glycemic control remains a shared challenge for clinicians and their patients with diabetes. Flash continuous glucose monitoring (CGM) provides immediate information about an individual's current and projected glucose level, allowing users to respond promptly to mitigate or prevent pending hypoglycemia or hyperglycemia. Large randomized controlled trials (RCTs) have demonstrated the glycemic benefits of flash CGM use in both type 1 and type 2 diabetes. However, whereas RCTs are mostly focused on the efficacy of this technology in defined circumstances, real-world studies can assess its effectiveness in wider clinical settings. This review assesses the most recent real-world studies demonstrating the effectiveness of flash CGM use to improve clinical outcomes and health care resource utilization in populations with diabetes.

Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.

The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway essential for cancer cell growth and survival. MLN4924 is a selective inhibitor of NAE currently in clinical trials for the treatment of cancer. Here, we show that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. Importantly, we have determined that compounds resembling MLN4924 demonstrate the ability to form analogous adducts with other ubiquitin-like proteins (UBLs) catalyzed by their cognate-activating enzymes. These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways.

Preventing Post-ERCP Pancreatitis: The Role of Prophylactic Pancreatic Duct Stenting in the Rectal NSAID Era.

BACKGROUND: Rectal non-steroidal anti-inflammatory drug at endoscopic retrograde cholangiopancreatography is now the standard of care to reduce the risk of post-ERCP pancreatitis. Pancreatic duct stenting also reduces the risk of post- ERCP pancreatitis in high-risk patients, but failed pancreatic duct stenting carries an increased PEP rate (up to 35%). STUDY AIM: To assess the impact on post-ERCP pancreatitis of successful and unsuccessful pancreatic duct stent placement in the setting of universal rectal non-steroidal anti-inflammatory drug use. METHODS: Between 2013-2015, all patients undergoing endoscopic retrograde cholangiopancreatographys in our tertiary referral centre (where rectal non-steroidal anti-inflammatory drugs are used routinely) were included. The electronic patient's records were reviewed and the following parameters were analysed: indication for pancreatic duct stenting; deployment success; and adverse events. RESULTS: A total of 1633 endoscopic retrograde cholangiopancreatographys were performed, and pancreatic duct stenting was attempted in 324 cases (20%), with successful placement in 307 patients (95%). Contra-indications to non-steroidal anti-inflammatory drugs were found in 106 (6.5%) patients. Prophylactic stenting failed in 12 of 213 patients; of whom one patient developed post-ERCP pancreatitis (8%). Eighteen (9%) patients with prophylactic pancreatic duct stents developed post-ERCP pancreatitis compared to 1.4% without prophylactic stents (RR 8.4, p=0.04). CONCLUSION: A lack of difference in post-ERCP pancreatitis in those who underwent successful, and unsuccessful, pancreatic duct stent placement may reflect the protective effect of non-steroidal anti-inflammatory drugs. This data adds to evidence suggesting that pancreatic duct stenting may be less important, even in high-risk patients, with the widespread use of non-steroidal anti-inflammatory drugs.

Mechanistic study of Uba5 enzyme and the Ufm1 conjugation pathway.

E1 enzymes activate ubiquitin or ubiquitin-like proteins (Ubl) via an adenylate intermediate and initiate the enzymatic cascade of Ubl conjugation to target proteins or lipids. Ubiquitin-fold modifier 1 (Ufm1) is activated by the E1 enzyme Uba5, and this pathway is proposed to play an important role in the endoplasmic reticulum (ER) stress response. However, the mechanisms of Ufm1 activation by Uba5 and subsequent transfer to the conjugating enzyme (E2), Ufc1, have not been studied in detail. In this work, we found that Uba5 activated Ufm1 via a two-step mechanism and formed a binary covalent complex of Uba5∼Ufm1 thioester. This feature contrasts with the three-step mechanism and ternary complex formation in ubiquitin-activating enzyme Uba1. Uba5 displayed random ordered binding with Ufm1 and ATP, and its ATP-pyrophosphate (PPi) exchange activity was inhibited by both AMP and PPi. Ufm1 activation and Uba5∼Ufm1 thioester formation were stimulated in the presence of Ufc1. Furthermore, binding of ATP to Uba5∼Ufm1 thioester was required for efficient transfer of Ufm1 from Uba5 to Ufc1 via transthiolation. Consistent with the two-step activation mechanism, the mechanism-based pan-E1 inhibitor, adenosine 5'-sulfamate (ADS), reacted with the Uba5∼Ufm1 thioester and formed a covalent, tight-binding Ufm1-ADS adduct in the active site of Uba5, which prevented further substrate binding or catalysis. ADS was also shown to inhibit the Uba5 conjugation pathway in the HCT116 cells through formation of the Ufm1-ADS adduct. This suggests that further development of more selective Uba5 inhibitors could be useful in interrogating the roles of the Uba5 pathway in cells.

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.

The effect of glycogen reduction on cardiorespiratory and metabolic responses during downhill running.

PURPOSE: Exercise-induced muscle damage and lowered glycogen are common during heavy training periods, and may prolong recovery. We examined the effects of lowered glycogen on cardiorespiratory, metabolic and perceptual responses to downhill running. METHODS: Twelve men performed two downhill runs (-12 % gradient, 12.1 ± 1.1 km h(-1)) separated by 6 weeks, under normal (NORM) and reduced glycogen (RED) conditions in a crossover design. For RED, participants performed exhaustive cycling at 60 % [Formula: see text]O2max power (95 ± 13 min) in the evening, and the next morning completed a downhill run comprising of five stages of 8 min running, with 2 min recovery (1 % gradient, 8 km h(-1)) between each stage. Expired gas, heart rate, rating of perceived exertion (RPE) and blood lactate (bLa) and glucose were measured for each stage. RESULTS: Blood glucose (P < 0.05) and respiratory exchange ratio (P < 0.01) were lower in RED, than NORM, throughout the downhill run. RED demonstrated higher bLa until stage Four (P < 0.05), and RPE for stages Two and Five (P < 0.05).Ventilatory equivalent of carbon dioxide output ([Formula: see text]/[Formula: see text]) was higher for stages One (P < 0.01), Two and Five (P < 0.05), and oxygen uptake ([Formula: see text] E/[Formula: see text]O2) was lower for stages Three and Four (P < 0.05) for RED. CONCLUSIONS: Downhill running with reduced glycogen, elevated fat oxidation and bLa response, and, in part, increased effort perception. The alterations in [Formula: see text] E/[Formula: see text]O2 and bLa may suggest that carbon dioxide removal was somewhat impaired.

The disease-modifying effect of dehydroepiandrosterone in different stages of experimentally induced osteoarthritis: a histomorphometric study.

BACKGROUND: Osteoarthritis (OA) is likely to become an increasing burden in the coming decades. Various agents have been developed to slow the progression of OA, and are collectively known as 'disease-modifying drugs', however, there is still little reliable evidence that such agents will be successful. Dehydroepiandrosterone (DHEA), a sex hormone precursor, has been recently proven as protective agent against OA, but the exact mechanism is still unkown. In the current study, the effects of weekly intra-articular injections of DHEA in preventing the progression of existing cartilage degeneration in an OA rabbit model were evaluated. The aim of the current study is to demonstrate the feature of its disease-modifying efficacy during OA progression. METHODS: Thirty male New Zealand white rabbits were used in this study. An anterior cruciate ligament transection (ACLT) model was used to create a progressive OA model in twenty rabbits. The animals were treated with DHEA or a placebo and were necropsied at 9 and 16 weeks. Ten rabbits receiving sham operations served as controls. The articular cartilage of the medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibial plateau (MTP) and lateral tibial plateau (LTP) was evaluated macroscopically and histologically. RESULTS: In the joints of the sham-operated rabbits, few histological changes were detected on the articular surfaces of the femoral condyles and tibial plateaus. ACLT obviously induced erosive changes on the cartilage surfaces. Compared to the placebo group, the macroscopic and Mankin score analyses demonstrated that the DHEA treatment markedly reduced the cartilage lesions and delayed cartilage degeneration in the four regions of the knee at 9 weeks after operation (macroscopic score: MFC P = 0.013; LFC P = 0.048; MTP P = 0.045; LTP P = 0.02, Mankin score: MFC P = 0.012; LFC P = 0.034; MTP P = 0.016; LTP P = 0.002). At 16 weeks, DHEA demonstrated chondroprotective effects on the lateral compartment of the knee compared to the placebo group, whereas the cartilage degeneration at the medial compartment of the knee did not differ among the groups (macroscopic score: LFC P = 0.046; LTP = 0.034, Mankin score: LFC P = 0.005; LTP P = 0.002). CONCLUSION: The disease-modifying efficacy of DHEA aganist OA is time-specific and site-dependent. DHEA could be used as a disease-modifying strategy to limit the progression of OA, especially in the middle stage.

Addressing the Burden of Multiple Daily Insulin Injections in Type 2 Diabetes with Insulin Pump Technology: A Narrative Review.

The growing prevalence of type 2 diabetes (T2D) remains a leading health concern in the US. Despite new medications and technologies, glycemic control in this population remains suboptimal, which increases the risk of poor outcomes, increased healthcare resource utilization, and associated costs. This article reviews the clinical and economic impacts of suboptimal glycemic control in patients on basal-bolus insulin or multiple daily injections (MDI) and discusses how new technologies, such as tubeless insulin delivery devices, referred to as "patch pumps", have the potential to improve outcomes in patients with T2D.