Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis.

BACKGROUND: Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits but their comparative effects on mortality in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD) are unknown. Hence, we evaluated and compared lifetime benefits arising from metformin or SGLT2 inhibitors in T2DM patients with CVD. MATERIALS AND METHODS: Studies published in the PubMed, EMBASE and CENTRAL databases before 28 October 2023 were retrieved. Treatment effects of metformin against US FDA-approved SGLT2 inhibitors in T2DM patients with CVD were evaluated and lifetime gains in event-free survival were estimated from our primary endpoints of all-cause and cardiovascular mortality. Risk ratios were derived to assess their impact on secondary outcomes such as major adverse cardiovascular events and hospitalizations for heart failure. RESULTS: Overall, 14 studies were included. Five studies published Kaplan-Meier curves for the primary outcome of all-cause mortality. Individual participant data were reconstructed from these Kaplan-Meier curves, from which we conducted our two-stage meta-analysis. Participants receiving metformin and SGLT2 inhibitors experienced a reduction in the risk for all-cause mortality as compared with those not taking metformin and placebo. However, participants receiving SGLT2 inhibitors had a higher all-cause mortality (hazard ratio 1.308, 95% confidence interval 1.103-1.550) versus metformin. Treatment with metformin was estimated to offer an additional 23.26 months of survival free from all-cause mortality versus 23.04 months with SGLT2 inhibitors. CONCLUSIONS: In patients with T2DM and CVD, metformin and SGLT2 inhibitors were associated with substantially lower all-cause mortality rates and slightly longer life expectancies than in patients without. Metformin presented an advantage over SGLT2 inhibitors in reducing all-cause mortality.

A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

'Insight' in medical training: what, why, and how?

The term 'insight' is generically defined in English language as the ability to perceive deeper truths about people and situations. In clinical practice, patient insight is known to have important implications in treatment compliance and clinical outcomes, and can be assessed clinically by looking for the presence of illness awareness, correct attribution of symptoms to underlying condition, and acceptance of treatment. In this article, we suggest that cultivating insight is actually a highly important, yet often overlooked, component of medical training, which may explain why some consistently learn well, communicate effectively, and quickly attain clinical competency, while others struggle throughout their clinical training and may even be difficult to remediate. We herein define 'insight' in the context of medical training as having an astute perception of personal cognitive processes, motivations, emotions, and ability (strengths, weaknesses, and limitations) that should drive self-improvement and effective behavioural regulation. We then describe the utility of cultivating 'insight' in medical training through three lenses of (i) promoting self-regulated, lifelong clinical learning, (ii) improving clinical competencies and person-centred care, and (iii) enhancing physician mental health and well-being. In addition, we review educational pedagogies that are helpful to create a medical eco-system that promotes the cultivation of insight among its trainees and practitioners. Finally, we highlight several tell-tale signs of poor insight and discuss psychological and non-psychological interventions that may help those severely lacking in insight to become more amenable to change and remediation.

Left Ventricular Ejection Fraction Association with Acute Ischemic Stroke Outcomes in Patients Undergoing Thrombolysis.

(1) Background: Little is known about how left ventricular systolic dysfunction (LVSD) affects functional and clinical outcomes in acute ischemic stroke (AIS) patients undergoing thrombolysis; (2) Methods: A retrospective observational study conducted between 2006 and 2018 included 937 consecutive AIS patients undergoing thrombolysis. LVSD was defined as left ventricular ejection fraction (LVEF) < 50%. Univariate and multivariate binary logistic regression analysis was performed for demographic characteristics. Ordinal shift regression was used for functional modified Rankin Scale (mRS) outcome at 3 months. Survival analysis of mortality, heart failure (HF) admission, myocardial infarction (MI) and stroke/transient ischemic attack (TIA) was evaluated with a Cox-proportional hazards model; (3) Results: LVSD patients in comparison with LVEF ≥ 50% patients accounted for 190 and 747 patients, respectively. LVSD patients had more comorbidities including diabetes mellitus (100 (52.6%) vs. 280 (37.5%), p < 0.001), atrial fibrillation (69 (36.3%) vs. 212 (28.4%), p = 0.033), ischemic heart disease (130 (68.4%) vs. 145 (19.4%), p < 0.001) and HF (150 (78.9%) vs. 46 (6.2%), p < 0.001). LVSD was associated with worse functional mRS outcomes at 3 months (adjusted OR 1.41, 95% CI 1.03-1.92, p = 0.030). Survival analysis identified LVSD to significantly predict all-cause mortality (adjusted HR [aHR] 3.38, 95% CI 1.74-6.54, p < 0.001), subsequent HF admission (aHR 4.23, 95% CI 2.17-8.26, p < 0.001) and MI (aHR 2.49, 95% CI 1.44-4.32, p = 0.001). LVSD did not predict recurrent stroke/TIA (aHR 1.15, 95% CI 0.77-1.72, p = 0.496); (4) Conclusions: LVSD in AIS patients undergoing thrombolysis was associated with increased all-cause mortality, subsequent HF admission, subsequent MI and poorer functional outcomes, highlighting a need to optimize LVEF.

Systematic review of isolated disseminated carcinomatosis of bone marrow from colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) metastasis commonly occurs in the liver and lungs with bone metastasis rarely occurring in isolation. Disseminated carcinomatosis of bone marrow (DCBM) is extremely rare in CRC. We conducted a systematic review to provide more information on the diagnosis, treatment options, and prognosis of the condition. METHODS: Studies were identified by performing searches on MEDLINE and EMBASE electronic databases according to the PRISMA statement standards. We included a single patient whom we treated for metastatic CRC presenting with DCBM in our study. Statistical analysis was performed using SPSS software version 23.0. RESULTS: A search through 5502 unique studies yielded 14 studies that were eventually included. There was a total of 17 cases of DCBM in CRC with back pain and constitutional symptoms as the most common presenting complaints. DCBM in CRC was associated with markedly elevated CEA of 275.57 (95% CI 17.13-534.00). There was no predilection for site of primary tumour. Overall median survival was 120 days (95% CI 64.43-175.58). The median survival for patients who received chemotherapy was 240 days (95% CI 71.11-408.89), as compared to 9 days (95% CI 1.80-16.20) for patients who received best supportive treatment. CONCLUSION: DCBM from CRC is extremely rare. Bone marrow examination remains the gold standard for diagnosis. Colonic stenting or surgical diversion may be more appropriate than primary resection in obstructed CRC in view of the poor prognosis. Systemic chemotherapy shows promise in increasing median survival.

Percutaneous coronary intervention in patients aged 80 years old and above: a systematic review and meta-analysis.

Background: Ischaemic heart disease remains the main cause of death in the world. With increasing age, frailty and comorbidities, senior patients aged 80 years old and above who undergo percutaneous coronary intervention (PCI) are at higher risk of mortality and other complications. Aims: We aimed to examine the overall outcomes for this group of patients. Methods: Four databases (PUBMED, EMBASE, SCOPUS and CENTRAL) were searched. Studies with patients aged 80 years old and above who underwent PCI for all indications were included. Pooled outcomes of all-cause death, cardiac death, in-hospital death, subsequent stroke/transient ischaemic attack (TIA), subsequent myocardial infarction (MI), subsequent congestive cardiac failure (CCF), and overall major adverse cardiac events (MACE) were obtained for meta-analysis. Results: From 2,566,004 patients, the pooled cumulative incidence of death was 19.22%, cardiac death was 7.78%, in-hospital death was 7.16%, subsequent stroke/TIA was 1.54%, subsequent MI was 3.58%, subsequent CCF was 4.74%, and MACE was 17.51%. The mortality rate of all patients was high when followed up for 3 years (33.27%). ST-elevation myocardial infarction patients had more outcomes of in-hospital death (14.24% vs 4.89%), stroke/TIA (1.93% vs 0.12%), MI (3.68 vs 1.55%) and 1-year mortality (26.16% vs 13.62%), when compared to non-ST-elevation myocardial infarction patients. Conclusions: There was a high mortality rate at 1 year and 3 years post-PCI in the overall population of senior patients aged 80 years old and above, regardless of indication. This necessitates further studies to explore the implications of these observations.

Propensity-score-matched analysis of D2 and D3 right hemicolectomy for colon cancer.

BACKGROUND: Complete mesocolic excision with D3 lymph node dissection in right-sided colon cancer is associated with improved oncological outcomes, but can potentially be associated with higher rates of complications compared to conventional D2 right hemicolectomy. This study aims to evaluate the oncological and perioperative outcomes of patients who underwent D3 right hemicolectomy, comparing to conventional right hemicolectomy. METHODS: From 2015 to 2020, 360 patients underwent right hemicolectomy for colonic malignancies. Data was retrospectively analysed from a prospectively collected database. A propensity-score-matched analysis was performed between the two groups to evaluate their outcomes. RESULTS: About 88(24.4%) patients underwent D3 right hemicolectomy, with the rest undergoing D2 right hemicolectomy. After propensity-matched analysis, D3 right hemicolectomy had a higher lymph node yield (median of 26 versus 23, p = 0.005), lower overall recurrence rate (11.7% versus 25.7%, p = 0.03), and lower overall mortality rate (14.5% versus 30.1%, p = 0.02) There were no significant differences in the complication rates. There were no anastomotic leaks. D3 right hemicolectomy was associated with an improved 3-year disease-free survival (DFS) with a hazard ratio of 0.63 (P = 0.21), and also an improved 3-year overall survival (OS) with a hazard ratio of 0.68 (P = 0.31). CONCLUSION: D3 right hemicolectomy is associated with a higher lymph node yield, without increasing morbidity or mortality. It is also associated with significantly lower recurrence and overall mortality rates in this study. Short term 3-year DFS and OS also trend towards favouring D3 right hemicolectomy. However, this study is limited by the small sample size and retrospective nature.

Cardiac Arrest Occurring in High-Rise Buildings: A Scoping Review.

Out-of-hospital cardiac arrests (OHCAs) occurring in high-rise buildings are a challenge to Emergency Medical Services (EMS). Contemporary EMS guidelines lack specific recommendations for systems and practitioners regarding the approach to these patients. This scoping review aimed to map the body of literature pertaining to OHCAs in high-rise settings in order to clarify concepts and understanding and to identify knowledge gaps. Databases were searched from inception through to 6 May 2021 including OVID Medline, PubMed, Embase, CINAHL, and Scopus. Twenty-three articles were reviewed, comprising 8 manikin trials, 14 observational studies, and 1 mathematical modelling study. High-rise settings commonly have lower availability of bystanders and automatic external defibrillators (AEDs), while height constraints often lead to delays in EMS interventions and suboptimal cardiopulmonary resuscitation (CPR), scene access, and extrication. Four studies found return of spontaneous circulation (ROSC) rates to be significantly poorer, while seven studies found rates of survival-to-hospital discharge (n = 3) and neurologically favourable survival (n = 4) to be significantly lower in multistorey settings. Mechanical chest compression devices, transfer sheets, and strategic defibrillator placement were suggested as approaches to high-rise OHCA management. A shift to maximising on-scene treatment time, along with bundling novel prehospital interventions, could ameliorate some of these difficulties and improve clinical outcomes for patients.

Prognostic Implications of Bicuspid and Tricuspid Aortic Valve Phenotype on Progression of Moderate Aortic Stenosis and Ascending Aorta Dilatation.

Studies on the impact of aortic valve anatomy (bicuspid aortic valve [BAV] or tricuspid aortic valve [TAV]) on the progression of moderate aortic stenosis (AS) and ascending aorta (AA) dilatation and its prognostic implications are limited. From 1991 to 2016, 288 asymptomatic patients with moderate AS detected during index echocardiography with at least 1 year of echocardiographic follow-up were retrospectively studied. Baseline clinical and echocardiographic characteristics were compared between patients with BAV (n = 80) and patients with TAV (n = 208). Co-primary outcomes were 1-year hemodynamic and anatomic progression of AS and AA dilatation. Secondary end points were the incidence of AA rapid progressors, all-cause mortality, aortic valve replacement, and congestive heart failure. Determinants of AS progression, AA diameters, AA dilatation, and prognostic outcomes were evaluated. Similar 1-year progression of the aortic valve peak velocity, Vmax (9 ± 18 vs 9 ± 23 cm/s), mean gradient (1.5 ± 2.3 vs 1.3 ± 3.2 mm Hg), and aortic valve area (AVA) (-0.04 ± 0.09 vs -0.05 ± 0.10 cm2) were noted for BAV and TAV groups, respectively. One-year progressions of AA were similar at Valsalva (0.11 ± 0.88 vs 0.14 ± 1.10 mm) and tubular levels (0.12 ± 0.68 vs 0.30 ± 1.51 mm) in BAV and TAV groups, respectively. A trend toward increased rapid AA progression in patients with BAV (31.3%) was observed compared with patients with TAV (14.8%, p = 0.099). BAV was associated with progression of Vmax (ß = 0.17, p = 0.036), the dimensionless index (ß = -0.17, p = 0.008), and AVA (ß = -0.14, p = 0.048), but not mean gradient after adjusting for age, baseline severity indexes, gender, hypertension, diabetes, and body surface area. Although BAV was a determinant of larger baseline AA diameter, there was no significant association between BAV and AA rapid progressors. Adjusted Kaplan-Meier curves demonstrated no differences in congestive heart failure, aortic valve replacement, or mortality between valve morphology. In conclusion, there was a similar 1-year disease progression in terms of AVA, Vmax, mean gradient, and AA diameters between patients with BAV and patients with TAV. BAV was associated with a significant increase in Vmax, dimensionless index, and AVA after adjusting for important confounders. Close and prolonged follow-up is warranted in both groups of patients.