Etiology of Mild and Moderate Anaemia Among Rural Adolescent Girls in India.

A cluster randomized control trial study was conducted in Ballabgarh block of Faridabad District, Haryana, India. Baseline data of a total of 198 non-anemic and 202 anemic adolescent girls (12-19 years) was analyzed for hemoglobin and serum level of hepcidin, ferritin, folate acid, soluble transferrin receptor, vitamin B12 and CRP. Deficiency of iron (p < 0.001), folate (p < 0.01) and their mixed deficiency (p < 0.001) significantly increased with increasing severity of anaemia and contributed to 48.7% mild anaemia and 66.9% moderate anaemia. Anaemia of inflammation contributed to 16.2% of mild anaemia and 11.7% of moderate anaemia. More than one third of mild anaemia is caused by other causes. Current iron and folic acid program can alleviate around more than 2/3rd moderate anaemia and around half of mild anaemia among adolescent girls. Unknown causes of anaemia need further investigation.

Racial/Ethnic Disparities in Aortic Valve Replacement Among Medicare Beneficiaries in the United States, 2012-2019.

PURPOSE: There are concerns that transcatheter or surgical aortic valve replacement (TAVR/SAVR) procedures are preferentially available to White patients. Our objective was to examine differences in utilization of aortic valve replacement and outcomes by race/ethnicity in the US for patients with aortic stenosis. METHODS: We performed a serial cross-sectional cohort study of 299,976 Medicare beneficiaries hospitalized with principal diagnosis of aortic stenosis between 2012 and 2019 stratified by self-reported race/ethnicity (Black, Hispanic, Asian, Native American, and White). Outcomes included aortic valve replacement rates within 6 months of index hospitalization and associated procedural outcomes, including 30-day readmission, 30-day and 1-year mortality. RESULTS: Within 6 months of an index admission for aortic stenosis, 86.8% (122,457 SAVR; 138,026 TAVR) patients underwent aortic valve replacement. Overall, compared with White people, Black (HR 0.87 [0.85-0.89]), Hispanic (0.92 [0.88-0.96]), and Asian (0.95 [0.91-0.99]) people were less likely to receive aortic valve replacement. Among patients who were admitted emergently/urgently, White patients (41.1%, 95% CI, 40.7-41.4) had a significantly higher aortic valve replacement rate compared with Black (29.6%, 95% CI, 28.3-30.9), Hispanic (36.6%, 95% CI, 34.0-39.3), and Asian patients (35.4%, 95% CI, 32.3-38.9). Aortic valve replacement rates increased annually for all race/ethnicities. There were no significant differences in 30-day or 1-year mortality by race/ethnicity. CONCLUSIONS: Aortic valve replacement rates within 6 months of aortic stenosis admission are lower for Black, Hispanic, and Asian people compared to White people. These race-related differences in aortic stenosis treatment reflect complex issues in diagnosis and management, warranting a comprehensive reassessment of the entire care spectrum for disadvantaged populations.

Bicuspid aortic stenosis: National three-year outcomes of transcatheter versus surgical aortic valve replacement among Medicare beneficiaries.

OBJECTIVE: Randomized trials of transcatheter versus surgical aortic valve replacements have excluded bicuspid anatomy. We compared 3-year outcomes of transcatheter aortic valve replacement versus surgical aortic valve replacement in patients aged more than 65 years with bicuspid aortic stenosis. METHODS: The Centers for Medicare and Medicaid data were used to identify 6450 patients undergoing isolated surgical aortic valve replacement (n = 3771) or transcatheter aortic valve replacement (n = 2679) for bicuspid aortic stenosis (2012-2019). Propensity score matching with 21 baseline characteristics including frailty created 797 pairs. RESULTS: Unmatched patients undergoing transcatheter aortic valve replacement were older than patients undergoing surgical aortic valve replacement (78 vs 70 years), with more comorbidities and frailty (all P < .001). After matching, transcatheter aortic valve replacement was associated with a similar mortality risk compared with surgical aortic valve replacement within the first 6 months (hazard ratio [HR], 1.08, 95% CI, 0.67-1.69) but a higher mortality risk between 6 months and 3 years (HR, 2.16, 95% CI, 1.22-3.83). Additionally, transcatheter aortic valve replacement was associated with a lower risk of heart failure readmissions before 6 months (HR, 0.51, 95% CI, 0.31-0.87) but a higher risk between 6 months and 3 years (HR, 4.78, 95% CI, 2.21-10.36). The 3-year risks of aortic valve reintervention (HR, 1.03, 95% CI, 0.30-3.56) and stroke (HR, 1.21, 95% CI, 0.75-1.96) were similar. CONCLUSIONS: Among matched Medicare beneficiaries undergoing transcatheter aortic valve replacement or surgical aortic valve replacement for bicuspid aortic stenosis, 3-year mortality was higher after transcatheter aortic valve replacement. However, transcatheter aortic valve replacement was associated with a similar risk of mortality and a lower risk of heart failure readmissions during the first 6 months after the intervention. Randomized comparative data are needed to best inform treatment choice.

Perineural low dexamethasone dose as adjuvant in supraclavicular brachial plexus block for arteriovenous fistula creation in end stage renal disease: a randomized controlled trial

Abstract Background and aims: Dexamethasone as adjunct to local anesthetic solution improves the quality of brachial plexus block (BPB). However, evidence for its efficacy at low doses (< 4 mg) is lacking. This study was designed to evaluate the duration of analgesia attained with low dose dexamethasone as adjuvant to local anesthetic for creation of arteriovenous fistula (AVF) under BPB. Methods: Sixty-six patients scheduled for AVF creation were randomly allocated to receive either saline (control) or 2 mg dexamethasone, together with 0.5% ropivacaine and 0.2% lignocaine. The primary outcome was duration of analgesia, defined as time from performing the block to the first analgesic request. The secondary outcomes were time from injection to complete sensory block, time from injection to complete motor block, duration of motor block, postoperative analgesic consumption, and fistula patency at three months. Results: All the blocks were effective. In the group that received dexamethasone, the time to first analgesic request was significantly delayed (432 ± 43.8 minutes vs. 386.4 ± 40.2 minutes; p < 0.01). The onset of sensory and motor blockade occurred faster in dexamethasone group and overall analgesic consumption was also reduced. However, dexamethasone addition did not prolong the duration of motor block. There was no statistically significant difference in the patency of fistulas between the two groups at three months. (p = 0.34). Conclusion: Addition of low-dose perineural dexamethasone to local anesthetic solution significantly prolonged the duration of analgesia. Further trials are warranted to compare the adverse effects between dexamethasone doses of 4 mg and lower.

Host Lipid Manipulation by Intracellular Bacteria: Moonlighting for Immune Evasion.

Lipids are complex organic molecules that fulfill energy demands and sometimes act as signaling molecules. They are mostly found in membranes, thus playing an important role in membrane trafficking and protecting the cell from external dangers. Based on the composition of the lipids, their fluidity and charge, their interaction with embedded proteins vary greatly. Bacteria can hijack host lipids to satisfy their energy needs or to conceal themselves from host cells. Intracellular bacteria continuously exploit host, from their entry into host cells utilizing host lipid machinery to exiting through the cells. This acquisition of lipids from host cells helps in their disguise mechanism. The current review explores various mechanisms employed by the intracellular bacteria to manipulate and acquire host lipids. It discusses their role in manipulating host membranes and the subsequence impact on the host cells. Modulating these lipids in macrophages not only serve the purpose of the pathogen but also modulates the macrophage energy metabolism and functional state. Additionally, we have explored the intricate pathogenic relationship and the potential prospects of using this knowledge in lipid-based therapeutics to disrupt pathogen dominance.

Leaflet thrombosis in transcatheter aortic valve intervention: mechanisms, prevention, and treatment options.

Introduction: Transcatheter aortic valve intervention (TAVR) has emerged as a promising alternative to surgical aortic valve replacement for patients with severe aortic stenosis. However, leaflet thrombosis has raised concerns about the long-term durability and outcomes of TAVR. This study aims to provide an overview of the mechanisms, prevention strategies, and treatment options for leaflet thrombosis in TAVR. Clinical evidence: Leaflet thrombosis refers to the formation of blood clots on bioprosthetic valve leaflets, leading to impaired leaflet mobility, early valve degeneration and dysfunction, and potential clinical implications. While the mechanisms underlying thrombus formation on valve leaflets are not fully understood, several factors, such as altered blood flow patterns within valve neosinuses, prothrombotic surfaces, and patient-related causes, have been implicated. Two distinct entities have been identified, namely, hypoattenuated leaflet thickening and restricted leaflet motion. Their occurrence appears dynamic over time and is related to the valve type. Imaging, including transesophageal echocardiography and multidetector computed tomography, plays a crucial role in the diagnosis and follow-up of leaflet thrombosis. Prevention and treatment options: Preventing leaflet thrombosis requires a comprehensive and tailored approach involving identifying high-risk patients, close monitoring, and antithrombotic therapy. Antithrombotic therapy with dual antiplatelet agents or anticoagulation is commonly employed in TAVR patients, although the optimal regimen is yet to be defined. Novel antithrombotic agents, such as direct oral anticoagulants, are being investigated for their efficacy and safety in preventing leaflet thrombosis. When leaflet thrombosis is detected, treatment options include intensified antithrombotic therapy, valve-in-valve intervention, or balloon valvuloplasty. The long-term outcomes and impact of leaflet thrombosis on valve durability and patient prognosis are areas of ongoing research. Summary: Leaflet thrombosis in TAVR is a considerable complication affecting valve function and patient outcomes. Understanding the mechanisms underlying thrombus formation and implementing appropriate prevention strategies are essential for mitigating this risk. Treatment options aim to restore leaflet mobility and optimize valve performance. Further research is needed to establish standardized protocols for antithrombotic therapy, identify high-risk patient populations, and determine the long-term consequences of leaflet thrombosis on TAVR outcomes.

Invasive Coronary Assessment in Myocardial Ischemia with No Obstructive Coronary Arteries.

PURPOSE OF REVIEW: The purpose of this review is threefold: (i) to give an overview of well-established invasive methods for assessing patients with ischemia with no obstructive coronary arteries (INOCA) in the cardiac catheterization laboratory; (ii) to describe the prognostic and treatment implications based on these findings, and (iii) to discuss current knowledge gaps and future perspectives. RECENT FINDINGS: Recent studies have demonstrated that invasive coronary function testing not only allows for risk stratification of patients with INOCA but also guides medical therapy with improvement in symptoms and quality of life. Based on these findings, invasive coronary function assessment is now a class 2a recommendation in the 2021 ACC/AHA chest pain guideline to improve the diagnosis of coronary microvascular dysfunction and to enhance risk stratification. Invasive functional testing for patients with INOCA is well established and easily performed in the catheterization laboratory. Comprehensive invasive assessment is a key to differentiating INOCA endotypes and optimizing both medical therapy and preventive strategies including lifestyle modification.

Sex-Specific Associations of Obstructive Sleep Apnea Risk With Patient Characteristics and Functional Outcomes After Acute Myocardial Infarction: Evidence From the VIRGO Study.

Background Though associations between obstructive sleep apnea (OSA) and cardiovascular outcomes are well described, limited data exist regarding the impact of OSA on sex-specific outcomes after acute myocardial infarction (AMI). Methods and Results The VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study enrolled 3572 adults aged 18 to 55 years with AMI from the United States and Spain during 2008 to 2012. We included patients for whom the Berlin Questionnaire for OSA was scored at the time of AMI admission (3141; 2105 women, 1036 men). We examined the sex-specific association between baseline OSA risk with functional outcomes including health status and depressive symptoms at 1 and 12 months after AMI. Among both groups, 49% of patients were at high risk for OSA (1040 women; 509 men), but only 4.7% (148) of patients had a diagnosed history of OSA. Though patients with a high OSA risk reported worse physical and mental health status and depression than low-risk patients in both sexes, the difference in these functional outcomes was wider in women than men. Moreover, women with a high OSA risk had worse health status, depression, and quality of life than high-risk men, both at baseline and at 1 and 12 months after AMI. Conclusions Young women with a high OSA risk have poorer health status and more depressive symptoms than men at the time of AMI, which may place them at higher risk of poorer health outcomes over the year following the AMI. Further, the majority of patients at high risk of OSA are undiagnosed at the time of presentation of AMI.

Outcomes of repeat transcatheter aortic valve replacement with balloon-expandable valves: a registry study.

BACKGROUND: With increasing numbers of patients undergoing transcatheter aortic valve replacement (TAVR), data on management of failed TAVR, including repeat TAVR procedure, are needed. The aim of this study was to assess the safety and efficacy of redo-TAVR in a national registry. METHODS: This study included all consecutive patients in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from Nov 9, 2011, to Dec 30, 2022 who underwent TAVR with balloon-expandable valves in failed transcatheter heart valves (redo-TAVR) or native aortic valves (native-TAVR). Procedural, echocardiographic, and clinical outcomes were compared between redo-TAVR and native-TAVR cohorts using propensity score matching. FINDINGS: Among 350 591 patients (1320 redo-TAVR; 349 271 native-TAVR), 1320 propensity-matched pairs of patients undergoing redo-TAVR and native-TAVR were analysed (redo-TAVR cohort: mean age 78 years [SD 9]; 559 [42·3%] of 1320 female, 761 [57·7%] male; mean predicted surgical risk of 30-day mortality 8·1%). The rates of procedural complications of redo-TAVR were low (coronary compression or obstruction: four [0·3%] of 1320; intraprocedural death: eight [0·6%] of 1320; conversion to open heart surgery: six [0·5%] of 1319) and similar to native-TAVR. There was no significant difference between redo-TAVR and native-TAVR populations in death at 30 days (4·7% vs 4·0%, p=0·36) or 1 year (17·5% vs 19·0%, p=0·57), and stroke at 30 days (2·0% vs 1·9%, p=0·84) or 1 year (3·2% vs 3·5%, p=0·80). Redo-TAVR reduced aortic valve gradients at 1 year, although they were higher in the redo-TAVR group compared with the native-TAVR group (15 mm Hg vs 12 mm Hg; p<0·0001). Moderate or severe aortic regurgitation rates were similar between redo-TAVR and native-TAVR groups at 1 year (1·8% vs 3·3%, p=0·18). Death or stroke after redo-TAVR were not significantly affected by the timing of redo-TAVR (before or after 1 year of index TAVR), or by index transcatheter valve type (balloon-expandable or non-balloon-expandable). INTERPRETATION: Redo-TAVR with balloon-expandable valves effectively treated dysfunction of the index TAVR procedure with low procedural complication rates, and death and stroke rates similar to those in patients with a similar clinical profile and predicted risk undergoing TAVR for native aortic valve stenosis. Redo-TAVR with balloon-expandable valves might be a reasonable treatment for failed TAVR in selected patients. FUNDING: Edwards Lifesciences.

Assessment of potential predictors affecting preoperative anxiety in Indian children- A prospective observational study.

Background and Aims: Preoperative anxiety is a common problem among children undergoing surgery. The aim of the study was to assess the incidence and identify various predictors of preoperative anxiety in Indian children. Material and Methods: A prospective, observational study was conducted on 60 children of the American Society of Anesthesiologists Physical status 1/2, aged 2-6 years and scheduled for elective surgery under general anesthesia in a tertiary care teaching hospital. Preoperative parental anxiety was assessed using the State-Trait Anxiety Inventory questionnaire. The children's anxiety was assessed in the preoperative room, at the time of parental separation, and at the induction of anesthesia using modified Yale Preoperative Anxiety Scale (mYPAS) scoring by an anesthesiologist and a psychologist. Sedative premedication was employed prior to parental separation. Logistic regression analysis was carried out to identify the possible predictors of anxiety. Results: The incidence of high preoperative anxiety among the studied children was 76% in the preoperative room, 93% during parental separation, and 96% during anesthetic induction. Among the nine possible predictors identified on univariate regression, the presence of siblings was found to be a significant independent predictor on multivariate regression analysis (P = 0.04). The inter-rater agreement was excellent for the assessment of preoperative anxiety using mYPAS by the anesthesiologist and psychologist (weighted Kappa, k = 0.79). Conclusion: The incidence of preoperative anxiety in Indian children in the age group of 2-6 years is very high. The preop anxiety escalates progressively at parental separation and induction of anesthesia despite sedative premedication. The presence of siblings is a significant predictor of preoperative anxiety.

Severe aortic stenosis detection by deep learning applied to echocardiography.

BACKGROUND AND AIMS: Early diagnosis of aortic stenosis (AS) is critical to prevent morbidity and mortality but requires skilled examination with Doppler imaging. This study reports the development and validation of a novel deep learning model that relies on two-dimensional (2D) parasternal long axis videos from transthoracic echocardiography without Doppler imaging to identify severe AS, suitable for point-of-care ultrasonography. METHODS AND RESULTS: In a training set of 5257 studies (17 570 videos) from 2016 to 2020 [Yale-New Haven Hospital (YNHH), Connecticut], an ensemble of three-dimensional convolutional neural networks was developed to detect severe AS, leveraging self-supervised contrastive pretraining for label-efficient model development. This deep learning model was validated in a temporally distinct set of 2040 consecutive studies from 2021 from YNHH as well as two geographically distinct cohorts of 4226 and 3072 studies, from California and other hospitals in New England, respectively. The deep learning model achieved an area under the receiver operating characteristic curve (AUROC) of 0.978 (95% CI: 0.966, 0.988) for detecting severe AS in the temporally distinct test set, maintaining its diagnostic performance in geographically distinct cohorts [0.952 AUROC (95% CI: 0.941, 0.963) in California and 0.942 AUROC (95% CI: 0.909, 0.966) in New England]. The model was interpretable with saliency maps identifying the aortic valve, mitral annulus, and left atrium as the predictive regions. Among non-severe AS cases, predicted probabilities were associated with worse quantitative metrics of AS suggesting an association with various stages of AS severity. CONCLUSION: This study developed and externally validated an automated approach for severe AS detection using single-view 2D echocardiography, with potential utility for point-of-care screening.

Reclassification of moderate aortic stenosis based on data-driven phenotyping of hemodynamic progression.

The management and follow-up of moderate aortic stenosis (AS) lacks consensus as the progression patterns are not well understood. This study aimed to identify the hemodynamic progression of AS, and associated risk factors and outcomes. We included patients with moderate AS with at least three transthoracic echocardiography (TTE) studies performed between 2010 and 2021. Latent class trajectory modeling was used to classify AS groups with distinctive hemodynamic trajectories, which were determined by serial systolic mean pressure gradient (MPG) measurements. Outcomes were defined as all-cause mortality and aortic valve replacement (AVR). A total of 686 patients with 3093 TTE studies were included in the analysis. Latent class model identified two distinct AS trajectory groups based on their MPG: a slow progression group (44.6%) and a rapid progression group (55.4%). Initial MPG was significantly higher in the rapid progression group (28.2 ± 5.6 mmHg vs. 22.9 ± 2.8 mmHg, P < 0.001). The prevalence of atrial fibrillation was higher in the slow progression group; there was no significant between-group difference in the prevalence of other comorbidities. The rapid progression group had a significantly higher AVR rate (HR 3.4 [2.4-4.8], P < 0.001); there was no between-group difference in mortality (HR 0.7 [0.5-1.0]; P = 0.079). Leveraging longitudinal echocardiographic data, we identified two distinct groups of patients with moderate AS: slow and rapid progression. A higher initial MPG (≥ 24 mmHg) was associated with more rapid progression of AS and higher rates of AVR, thus indicating the predictive value of MPG in management of the disease.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

The regulation of m6A-related proteins during whole-body freezing of the freeze-tolerant wood frog.

Rana sylvatica (also known as Boreorana sylvatica) is one of the few vertebrates that spend extreme winters showing no physiological signs of life. Up to 70% of the total body water of the wood frog freezes as extracellular ice. Survival in extreme conditions requires regulation at transcriptional and translational levels to activate prosurvival pathways. N6-methyladenosine (m6A) methylation is one of the most common RNA modifications, regulating transcript processing and translation by executing important functions that affect regulatory pathways in stress conditions. In the study, regulation of m6A-related proteins in the liver of R. sylvatica was analyzed during 24 h frozen and 8 h thaw conditions. Decreases in the activity of demethylases of 28.44 ± 0.4% and 24.1 ± 0.9% of control values in frozen and thaw tissues, respectively, were observed. Total protein levels of m6A methyltransferase complex components methyltransferase-like 14 and Wilm's tumor associated protein were increased by 1.28-fold and 1.42-fold, respectively, during freezing. Demethylase fat mass and obesity, however, showed a decreasing trend, with a significant decrease in abundance during recovery from frozen conditions. Levels of mRNA degraders YTHDF2 and YTHDC2 also decreased under stress. Overall, increased levels of m6A methylation complex components, and suppressed levels of readers/erasers, provide evidence for the potential role of RNA methylation in freezing survival and its regulation in a hypometabolic state.

Perineural low dexamethasone dose as adjuvant in supraclavicular brachial plexus block for arteriovenous fistula creation in end stage renal disease: a randomized controlled trial.

BACKGROUND AND AIMS: Dexamethasone as adjunct to local anesthetic solution improves the quality of brachial plexus block (BPB). However, evidence for its efficacy at low doses (< 4 mg) is lacking. This study was designed to evaluate the duration of analgesia attained with low dose dexamethasone as adjuvant to local anesthetic for creation of arteriovenous fistula (AVF) under BPB. METHODS: Sixty-six patients scheduled for AVF creation were randomly allocated to receive either saline (control) or 2 mg dexamethasone, together with 0.5% ropivacaine and 0.2% lignocaine. The primary outcome was duration of analgesia, defined as time from performing the block to the first analgesic request. The secondary outcomes were time from injection to complete sensory block, time from injection to complete motor block, duration of motor block, postoperative analgesic consumption, and fistula patency at three months. RESULTS: All the blocks were effective. In the group that received dexamethasone, the time to first analgesic request was significantly delayed (432 ± 43.8 minutes vs. 386.4 ± 40.2 minutes; p < 0.01). The onset of sensory and motor blockade occurred faster in dexamethasone group and overall analgesic consumption was also reduced. However, dexamethasone addition did not prolong the duration of motor block. There was no statistically significant difference in the patency of fistulas between the two groups at three months. (p = 0.34). CONCLUSION: Addition of low-dose perineural dexamethasone to local anesthetic solution significantly prolonged the duration of analgesia. Further trials are warranted to compare the adverse effects between dexamethasone doses of 4 mg and lower.

Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study.

BACKGROUND: Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. OBJECTIVES: To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. METHODS: A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. RESULTS: In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. CONCLUSIONS: CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy. Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.

Activation of p53 in anoxic freshwater crayfish, Faxonius virilis.

Tumor suppressing transcription factor p53 regulates multiple pathways including DNA repair, cell survival, apoptosis and autophagy. Here, we studied the stress-induced activation of p53 in anoxic crayfish (Faxonius virilis). Relative levels of target proteins and mRNAs involved in the DNA damage response were measured in normoxic control and anoxic hepatopancreas and tail muscle. Phosphorylation levels of p53 were assessed using immunoblotting at sites known to be phosphorylated (serine 15 and 37) in response to DNA damage or reduced oxygen signaling. The capacity for DNA binding by phosphorylated p53 (p-p53) was also measured, followed by transcript analysis of a potentially pro-apoptotic downstream target, the etoposide induced (ei24) gene. Following this, both inhibitor (MDM2) and activator (p19-ARF) protein levels in response to low-oxygen stress were studied. The results showed an increase in p-p53 levels during anoxia in both hepatopancreas and tail muscle. Increased transcript levels of ei24 support the activation of p53 under anoxic stress. Cytoplasmic accumulation of Ser15 phosphorylated p53 was observed during anoxia when proteins from cytoplasmic and nuclear fractions were measured. Increased cytoplasmic concentration is known to initiate an apoptotic response, which can be assumed as a preparatory step to prevent autophagy. The results suggest that p53 might play a protective role in crayfish defense against low-oxygen stress. Understanding how anoxia-tolerant organisms are able to protect themselves against DNA damage could provide important clues towards survival under metabolic rate depression and preparation for recovery to minimize damage.