Translesion synthesis (TLS) DNA polymerases were originally described as error-prone enzymes involved in the bypass of DNA lesions. However, extensive research over the past few decades has revealed that these enzymes play pivotal roles not only in lesion bypass, but also in a myriad of other cellular processes. Such processes include DNA replication, DNA repair, epigenetics, immune signaling, and even viral infection. This review discusses the wide range of functions exhibited by TLS polymerases, including their underlying biochemical mechanisms and associated mutagenicity. Given their multitasking ability to alleviate replication stress, TLS polymerases represent a cellular dependency and a critical vulnerability of cancer cells. Hence, this review also highlights current and emerging strategies for targeting TLS polymerases in cancer therapy.

Freedom to err: The expanding cellular functions of translesion DNA polymerases.

Molecular Cell

Chronic kidney disease (CKD) is a common occurrence in patients with diabetes mellitus (DM), occurring in approximately 40% of cases. DM is also an important risk factor for cardiovascular disease (CVD), but CKD is an important mediator of this risk. Multiple CVD outcomes trials have revealed a greater risk for CVD events in patients with diabetes with CKD versus those without. Thus, reducing the risk of CKD in diabetes should result in improved CVD outcomes. To date, of blood pressure (BP) control, glycemic control, and inhibition of the renin-angiotensin system (RASI), glycemic control appears to have the best evidence for preventing CKD development. In established CKD, especially with albuminuria, RASI slows the progression of CKD. More recently, sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP1RA) have revolutionized the care of patients with diabetes with and without CKD. SGLT2i and GLP1RA have proven to reduce mortality, heart failure (HF) hospitalizations, and worsening CKD in patients with diabetes with and without existing CKD. The future of limiting CVD in diabetes and CKD is promising, and more evidence is forthcoming regarding combinations of evidence-based therapies to further minimize CVD events.

Cardiovascular Disease in Diabetes and Chronic Kidney Disease.

Journal of Clinical Medicine

Circulatory shock is a common and important diagnosis in the critical care environment. Hemodynamic monitoring is quintessential in the management of shock. The currently used hemodynamic monitoring devices not only measure cardiac output but also provide data related to the prediction of fluid responsiveness, extravascular lung water, and also pulmonary vascular permeability. Additionally, these devices are minimally invasive and associated with fewer complications. The area of hemodynamic monitoring is progressively evolving with a trend toward the use of minimally invasive devices in this area. The critical care physician should be well-versed with current hemodynamic monitoring limitations and stay updated with the upcoming advances in this field so that optimal therapy can be delivered to patients in circulatory shock.

Monitoring Macro- and Microcirculation in the Critically Ill: A Narrative Review.

Avicenna Journal of Medicine

Japanese research is no longer world class - here's why.

Nature

Urinary tract infections are the most common bacterial infections worldwide. Infections can range from mild, recurrent (rUTI) to complicated (cUTIs), and are predominantly caused by uropathogenic Escherichia coli (UPEC). Antibiotic therapy is important to tackle infection; however, with the continued emergence of antibiotic resistance there is an urgent need to monitor the use of effective antibiotics through better stewardship measures. Currently, clinical diagnosis of UTIs relies on empiric methods supported by laboratory testing including cellular analysis (of both human and bacterial cells), dipstick analysis and phenotypic culture. Therefore, development of novel, sensitive and specific diagnostics is an important means to rationalise antibiotic therapy in patients. This review discusses the current diagnostic landscape and highlights promising novel diagnostic technologies in development that could aid in treatment and management of antibiotic-resistant UTIs.

Urinary tract infections: a review of the current diagnostics landscape.

Journal of Medical Microbiology

Ketoacidosis induced by sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment has been consistently observed in clinical practice in patients with type 2 diabetes despite minimal indication from the landmark cardiovascular outcome trials. It has been postulated that individuals without diabetes will not develop this complication due to an adequate insulin secretory capacity, which will protect against significant ketone formation. Cardiovascular outcome trials examining SGLT2i use in individuals with heart failure but not diabetes have not reported ketoacidosis.

We describe the first two case reports of severe nondiabetic ketoacidosis after initiation of an SGLT2i for the treatment of heart failure with reduced ejection fraction, and we describe the management strategies employed and implication for the pathophysiology of SGLT2i-associated ketoacidosis.

Each individual presented with ketoacidosis triggered by reduced oral nutrition intake. For both individuals, ketoacidosis resolved with intravenous glucose administration, encouragement of consumption of oral glucose-containing fluid, and minimal insulin administration.

These two cases demonstrate that SGLT2i-associated ketoacidosis is possible in individuals without diabetes.

Euglycemic Ketoacidosis in Two Patients Without Diabetes After Introduction of Sodium-Glucose Cotransporter 2 Inhibitor for Heart Failure With Reduced Ejection Fraction.

Diabetes Care

Traumatic injury causes a significant number of deaths due to bleeding. Tranexamic acid (TXA), an antifibrinolytic agent, can reduce bleeding in traumatic injuries and potentially enhance outcomes. Previous reviews suggested potential TXA benefits but did not consider the latest trials.

A systematic review and bias-adjusted meta-analysis were performed to assess TXA's effectiveness in emergency traumatic injury settings by pooling estimates from randomized controlled trials. Researchers searched Medline, Embase, and Cochrane Central for randomized controlled trials comparing TXA's effects to a placebo in emergency trauma cases. The primary endpoint was 1-month mortality. The methodological quality of the trials underwent assessment using the MASTER scale, and the meta-analysis applied the quality-effects method to adjust for methodological quality.

Seven randomized controlled trials met the set criteria. This meta-analysis indicated an 11% decrease in the death risk at 1 month after TXA use (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.84 to 0.95) with a number needed to treat of 61 to avoid 1 additional death. The meta-analysis also revealed reduced 24-hour mortality (OR 0.76, 95% CI 0.65 to 0.88) for TXA. No compelling evidence of increased vascular occlusive events emerged (OR 0.96, 95% CI 0.73 to 1.27). Subgroup analyses highlighted TXA's effectiveness in general trauma versus traumatic brain injury and survival advantages when administered out-of-hospital versus inhospital.

This synthesis demonstrates that TXA use for trauma in emergencies leads to a reduction in 1-month mortality, with no significant evidence of problematic vascular occlusive events. Administering TXA in the out-of-hospital setting is associated with reduced mortality compared to inhospital administration, and less mortality with TXA in systemic trauma is noted compared with traumatic brain injury specifically.

Tranexamic Acid for Traumatic Injury in the Emergency Setting: A Systematic Review and Bias-Adjusted Meta-Analysis of Randomized Controlled Trials.

Annals of Emergency Medicine

We aimed to elucidate whether postinduction hypotension (PIH), defined as hypotension between anesthesia induction and skin incision, and intraoperative hypotension (IOH) are associated with postoperative mortality.

We conducted a retrospective cohort study of adult patients with an ASA Physical Status I-IV who underwent noncardiac and nonobstetric surgery under general anesthesia between 2015 and 2021 at Nagoya City University Hospital. The primary and secondary outcomes were 30-day and 90-day postoperative mortality, respectively. We calculated four hypotensive indices (with time proportion of the area under the threshold being the primary exposure variable) to evaluate the association between hypotension (defined as a mean blood pressure&#x2009;&lt;&#x2009;65&#xa0;mm Hg) and mortality using multivariable logistic regression models. We used propensity score matching and RUSBoost (random under-sampling and boosting), a machine-learning model for imbalanced data, for sensitivity analyses.

Postinduction hypotension and IOH were observed in 82% and 84% of patients, respectively. The 30-day and 90-day postoperative mortality rates were 0.4% (52/14,210) and 1.0% (138/13,334), respectively. Postinduction hypotension was not associated with 30-day mortality (adjusted odds ratio [aOR], 1.03; 95% confidence interval [CI], 0.93 to 1.13; P&#x2009;=&#x2009;0.60) and 90-day mortality (aOR, 1.01; 95% CI, 0.94 to 1.07; P&#x2009;=&#x2009;0.82). Conversely, IOH was associated with 30-day mortality (aOR, 1.19; 95% CI, 1.12 to 1.27; P&#x2009;&lt;&#x2009;0.001) and 90-day mortality (aOR, 1.12; 95% CI, 1.06 to 1.19; P&#x2009;&lt;&#x2009;0.001). Sensitivity analyses supported the association of IOH but not PIH with postoperative mortality.

Despite limitations, including power and residual confounding, postoperative mortality was associated with IOH but not with PIH.

Association between postinduction hypotension and postoperative mortality: a single-centre retrospective cohort study.

Canadian Journal of Anaesthesia

Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung's alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

Freedom to err: The expanding cellular functions of translesion DNA polymerases.

Full text links

For the best experience, use the Read mobile app

Freedom to err: The expanding cellular functions of translesion DNA polymerases.

Full text links

Trending Papers

For the best experience, use the Read mobile app