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The activation and functional differentiation of CD8+T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+T cells, which act as transcription initiators of key genes regulating CD8+T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+T cells.

BackgroundBurn injury is associated with significant mortality and disability. Resilient and responsive health systems are needed for optimal response and care for people who sustain burn injuries. However, the extent of health systems research (HSR) in burn care is unknown. This review aimed to systematically map the global HSR related to burn care.MethodsAn evidence gap map (EGM) was developed based on the World Health Organization health systems framework. All major medical, health and injury databases were searched. A standard method was used to develop the EGM.ResultsA total of 6586 articles were screened, and the full text of 206 articles was reviewed, of which 106 met the inclusion criteria. Most included studies were cross-sectional (61%) and were conducted in hospitals (71%) with patients (48%) or healthcare providers (29%) as participants. Most studies were conducted in high-income countries, while only 13% were conducted in low-and middle-income countries, accounting for 60% of burns mortality burden globally. The most common health systems areas of focus were service delivery (53%), health workforce (33%) and technology (19%). Studies on health policy, governance and leadership were absent, and there were only 14 qualitative studies.ConclusionsMajor evidence gaps exist for an integrated health systems response to burns care. There is an inequity between the burden of burn injuries and HSR. Strengthening research capacity will facilitate evidence-informed health systems and policy reforms to sustainably improve access to affordable, equitable and optimal burn care and outcomes.

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Atrioesophageal fistula is a rare, devastating complication of atrial fibrillation ablation, reportedly occurring in 0.015–0.04% of catheter ablations. A 66-year-old African American male with a past medical history of chronic atrial fibrillation status post recent radiofrequency ablation and on chronic anticoagulation with rivaroxaban presented with left upper extremity numbness, tingling, and transient weakness. He was admitted for a cerebrovascular accident workup; a 12-lead electrocardiogram revealed atrial fibrillation and magnetic resonance imaging of the brain was consistent with multifocal embolic infarcts. Hospital course was further complicated by persistent high-grade fevers, gram-positive bacteremia, and worsening mental status requiring mechanical ventilation. Lumbar puncture was consistent with bacterial meningitis. Transthoracic echocardiogram was negative for vegetations. Computed tomography angiography of the chest with intravenous contrast revealed an outpouching off the posterior wall of the left atrium at the level of the inferior pulmonary vein, consistent with an atrioesophageal fistula. We present this case to highlight the clinical features of a rare but potentially fatal complication from a commonly performed procedure requiring prompt recognition and life-saving intervention.

We have investigated the structure of the distal C-terminal domain of the of the CB1cannabinoid receptor (CB1R) to study its interactions with CRIP1a and CRIP1b using computational techniques. The amino acid sequence from the distal C-terminal domain of CB1R (G417-L472) was found to be unique, as it does not share sequence similarity with other protein structures, so the structure was predicted using ab initiomodeling. The computed model of the distal C-terminal region of CB1R has a helical region between positions 441 and 455. The CRIP1a and CRIP1b were modeled using Rho-GDI 2 as a template. The three-dimensional model of the distal C-terminal domain of the CB1R was docked with both CRIP1a as well as CRIP1b to study the crucial interactions between CB1R and CRIP1a/b. The last nine residues of CB1R (S464TDTSAEAL4722) are known to be a CRIP1a/b binding site. The majority of the key interactions were identified in this region, but notable interactions were also observed beyond theses nine residues. The multiple interactions between Thr418 (CB1R) and Asn61 (CRIP1a) as well as Asp430 (CB1R) and Lys76 (CRIP1a) indicate their importance in the CB1R–CRIP1a interaction. In the case of CRIP1b, multiple hydrogen bond interactions between Asn437 (CB1R) and Glu77 (CRIP1b) were observed. These interactions can be critical for CB1R’s interaction with CRIP1a/b, and targeting them for further experimental studies can advance information about CRIP1a/b functionality.

Introduction:MMPs are zinc-dependent endopeptidases that play a key role in the remodeling of extracellular matrix (ECM). Various pathogenic mediators trigger abnormal MMP activity that leads to ECM abnormality. Hyperglycemia is one of the strong stimuli among oxidative stress and inflammation that upregulate MMP expression in the central and peripheral nervous system. MMP-mediated ECM abnormality hypersensitizes peripheral as well as central nerves that precipitate neuropathic pain in diabetic patients.Areas covered:Molecular mechanisms associated with MMP-mediated diabetic neuropathic pain have been discussed. Various endogenous, natural and synthetic MMP inhibitors are also explored.Expert opinion:In diabetes, hyperglycemia activates MMPs that along with the other pathogenic mediators cause neuronal injury and precipitates neuropathic pain. Thus, MMPs play a crucial role in the development of neuropathic pain among diabetics. However, MMPs are not only responsible for deleterious ECM abnormalities but are also required for beneficial remodeling of ECM under normal physiological conditions. Therefore, highly selective and specific inhibitors must be designed and explored for their clinical potential for treatment/prevention of diabetic neuropathic pain.

Pseudomonas fluorescens (P. fluorescens)and Pseudomonas putida (P. putida)are uncommon causes of skin and soft tissue infections (SSTIs). They are rarely associated with bacteremia and fatality. When presenting with sepsis/shock, patients are usually immunocompromised. Our case highlights the importance of early recognition, source control and antimicrobial choice.

Acquired hemophilia A (AHA) also known as acquired factor VIII (FVIII) deficiency is an acquired inhibition of coagulation by antibodies that either inhibit the activity or increase the clearance of a clotting factor (FVIII). Mortality in patients presenting with AHA is related to bleeding and hemorrhage, therefore rapid diagnosis and effective treatment are needed.

Zieve's syndrome (ZS) is a triad of hemolytic anemia, cholestatic jaundice and hyperlipidemia that presents in the setting of alcohol abuse and liver disease. ZS is not well known and remains underdiagnosed. We present a case of ZS in a 38-year-old female with a history of chronic alcohol abuse and pancreatitis to raise awareness of ZS. It is important for ZS to be recognized promptly to avoid unnecessary and possibly harmful interventions.

Gastric diverticula are the least common gastrointestinal diverticula. Patients can be diagnosed incidentally on EGD or present with variable symptoms such as abdominal fullness, anorexia, and perforation. Gastric diverticula can be acquired from malignancy, peptic ulcer disease, or prior surgery or be congenital. Treatment varies based on symptomatology ranging from conservative medical management with proton pump inhibitors to surgical treatment with open or laparoscopic resection. We present a case of a 73-year-old female with acquired gastric diverticulum presenting as a gastric outlet obstruction who was successfully treated with conservative medical therapy.