Notes

Precision of the endoscopic look at esophageal engagement within esophagogastric jct cancer.
Patients with major risk factors for PAS warrant dedicated ultrasound imaging with a provider experienced in the prenatal diagnosis of PAS.
Patients with major risk factors for PAS warrant dedicated ultrasound imaging with a provider experienced in the prenatal diagnosis of PAS.
Anemia in pregnancy is associated with increased maternal and neonatal morbidity. There is increasing awareness amongst obstetricians about the need to screen for iron deficiency anemia (IDA), as well as growing literature on diagnosis and treatment. This review aims to summarize causes, consequences, treatment, and evaluation of IDA in pregnancy.

National guidelines provide varying guidance on diagnosis and treatment of IDA in pregnancy. Serum ferritin is a helpful adjunct for the diagnosis of IDA. Oral iron remains an option for treatment; absorption is improved with every other day dosing and is effective for patients able to tolerate. Emerging studies on modern generations of intravenous (IV) iron demonstrate shorter infusion times and improved safety profiles. Notably, recent UK guidelines provide consideration for universal IV iron supplementation for treatment of anemia beyond 34 weeks of pregnancy.

Iron, in dietary, oral, and IV forms, has been found effective in resolving anemia in pregnancy. Pregnant people with IDA in the third trimester are more likely to benefit from IV iron. Future studies designed and powered to assess maternal and perinatal morbidity indicators and blood transfusion rates can strengthen recommendations.
Iron, in dietary, oral, and IV forms, has been found effective in resolving anemia in pregnancy. Pregnant people with IDA in the third trimester are more likely to benefit from IV iron. Future studies designed and powered to assess maternal and perinatal morbidity indicators and blood transfusion rates can strengthen recommendations.
The principle of optimizing oxygen delivery to the injured brain rests on the premise that both hypoxia and hyperoxia are important mediators of secondary brain injury and should be avoided. This rationale has prompted a move towards incorporating oxygenation endpoints into the management of neurocritical care patients, particularly those with traumatic brain injury. The present review will seek to describe clinical strategies to optimize oxygenation in the acutely brain-injured patient, drawing upon relevant physiologic principles and clinical data, where it exists.

A phase II randomized trial found that a protocolized approach to improving oxygen delivery resulted in less duration of brain hypoxia and a trend towards lower mortality among patients with severe traumatic brain injury. Recent clinical protocols have been published to guide oxygen delivery based on core physiologic principles increasing oxygen supply via modulation of mean arterial pressure and intracranial pressure, blood oxygen carrying capacity, and cerebral vasoreactivity; and decreasing oxygen demand via sedation, pharmacologic coma, and hypothermia.

Although there is growing interest in the use of brain tissue oxygenation as a resuscitative endpoint, many of these therapies are based on physiologic principles with little robust clinical evidence to guide their application. Clinicians must be mindful of this and balance the putative benefits of improving oxygenation against the risks associated with the use of such therapies.
Although there is growing interest in the use of brain tissue oxygenation as a resuscitative endpoint, many of these therapies are based on physiologic principles with little robust clinical evidence to guide their application. Clinicians must be mindful of this and balance the putative benefits of improving oxygenation against the risks associated with the use of such therapies.
Drug-induced liver injury (DILI) remains a challenging diagnosis requiring exclusion of other causes of liver injury, concise medical history taking to identify potential causative medication and creation of a plausible temporal relation to attribute said liver injury to a potentially hepatotoxic agent. In spite of corticosteroids being considered an effective treatment for DILI in some patients, methylprednisolone (MPS) has been associated with liver injury of varying severity.

We analyzed data of our prospective study on potentially hepatotoxic drugs (NCT02353455), identified 13 cases of MPS-associated liver injury and performed an analysis of clinical, laboratory and histopathological characteristics. For all available liver biopsy specimens, expert histopathological analysis was performed.

Thirteen patients with a variety of primarily neurologic autoimmune diseases treated with MPS developed subsequent liver injury with a median latency of 5 weeks. Liver injury was severe or required transplantationso after discharge to avoid further MPS-related liver injury during repeat application. Swift response to prednisolone but not histologic features can be helpful to discriminate MPS-DILI from AIH.Kidney fibrosis is the final common pathway of progressive kidney diseases, the underlying mechanisms of which are not fully understood. The purpose of the current study is to investigate a role of Piezo1, a mechanosensitive nonselective cation channel, in kidney fibrosis. In human fibrotic kidneys, Piezo1 protein expression was markedly upregulated. LY294002 supplier The abundance of Piezo1 protein in kidneys of mice with unilateral ureter obstruction (UUO) or with folic acid treatment was significantly increased. Inhibition of Piezo1 with nonspecific inhibitor GsMTx4 markedly ameliorated UUO- or folic acid-induced kidney fibrosis. Mechanical stretch, compression, or stiffness induced Piezo1 activation and profibrotic responses in human HK2 cells and primary cultured mouse proximal tubular cells (mPTCs), which were greatly prevented by inhibition or silence of Piezo1. TGF-β1 induced increased Piezo1 expression and profibrotic phenotypic alterations in HK2 cells and mPTCs, which were again markedly prevented by inhibition of Piezo1. Activation of Piezo1 by Yoda1, a Piezo1 agonist, caused calcium influx and profibrotic responses in HK2 cells and induced calcium-dependent protease calpain2 activation, followed by adhesion complex protein talin1 cleavage and upregulation of integrin β1. Also, Yoda1 promoted the link between ECM and integrin β1. In conclusion, Piezo1 is involved in the progression of kidney fibrosis and profibrotic alterations in renal proximal tubular cells, likely through activating calcium/calpain2/integrin β1 pathway.Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.SARS-CoV-2 vaccines pose as the most effective approach for mitigating the COVID-19 pandemic. High-degree efficacy of SARS-CoV-2 vaccines in clinical trials indicates that vaccination invariably induces an adaptive immune response. However, the emergence of breakthrough infections in vaccinated individuals suggests that the breadth and magnitude of vaccine-induced adaptive immune response may vary. We assessed vaccine-induced SARS-CoV-2 T cell response in 21 vaccinated individuals and found that SARS-CoV-2-specific T cells, which were mainly CD4+ T cells, were invariably detected in all individuals but the response was varied. We then investigated differentiation states and cytokine profiles to identify immune features associated with superior recall function and longevity. We identified SARS-CoV-2-specific CD4+ T cells were polyfunctional and produced high levels of IL-2, which could be associated with superior longevity. Based on the breadth and magnitude of vaccine-induced SARS-CoV-2 response, we identified 2 distinct response groups individuals with high abundance versus low abundance of SARS-CoV-2-specific T cells. The fractions of TNF-α- and IL-2-producing SARS-CoV-2 T cells were the main determinants distinguishing high versus low responders. Last, we identified that the majority of vaccine-induced SARS-CoV-2 T cells were reactive against non-mutated regions of mutant S-protein, suggesting that vaccine-induced SARS-CoV-2 T cells could provide continued protection against emerging variants of concern.Germline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.The importance of healthy mitochondrial function is implicated in the prevention of chronic kidney disease (CKD) and diabetic kidney disease (DKD). Sex differences also play important roles in DKD. Our previous studies revealed that mitochondrial substrate overload (modeled by homozygous deletion of carnitine acetyl-transferase [CrAT]) in proximal tubules causes renal injury. Here, we demonstrate the importance of intact mitochondrial substrate efflux by titrating the amount of overload through the generation of a heterozygous CrAT-KO model (PT-CrATHET mouse). Intriguingly, these animals developed renal injury similarly to their homozygous counterparts. Mitochondria were structurally and functionally impaired in both sexes. Transcriptomic analyses, however, revealed striking sex differences. Male mice shut down fatty acid oxidation and several other metabolism-related pathways. Female mice had a significantly weaker transcriptional response in metabolism, but activation of inflammatory pathways was prominent.
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