Search

Abstract Human intestinal gut microbiota harbors complex and diverse microbes that play an important role in maintaining the homeostasis of the intestinal microenvironment in humans. The rise in mortality and morbidity rates among humans because of the increased incidence of food‐borne pathogens and the habits of individuals to eat junk food poses greater concerns and needs to be addressed. Bioengineering of probiotics has enabled the researchers to advance their research by developing probiotics with more functionalities. Moreover, GLP‐1 peptides which are incretin hormones have been shown to be more effective when combined with engineered probiotics. Various studies have shown its effectiveness in diabetic mice where human‐modified GLP‐1 produced long‐lasting benefits and research is going on to study its role in other diseases. The role of designer probiotics in treating and preventing diseases have been of much interest in recent times. However, the role of GLP‐1 peptides in treating diseases and their efficacy in combination with next‐gen biotherapeutics have received little attention. Thus, this review enlightens about the baseline knowledge as well as knowledge gaps related to conventional and genetically engineered probiotics. It also discusses the effect of GLP‐1 peptides in combination with bioengineered probiotics to prevent and treat diseases.

Abstract The quantum communication channel is considered to be eavesdropped when the signal Quantum Bit Error Rate (QBER) exceeds a defined theoretical limit and is thus considered a figure of merit parameter for assessing the security of a quantum channel. This work presents a general mathematical model considering device imperfections and various sources of errors for estimating signal QBER in polarisation encoded satellite‐based QKD systems. QBER performance for satellite‐to‐ground downlink scenarios has been investigated for multiple sky brightness conditions (day time and night time operations), two operating wavebands: 800 and 1550 nm as well as for different quantum transmitter and quantum receiver architectures. Further, a novel QBER estimation analysis for inter‐satellite QKD links has also been presented. The estimation results obtained from the developed model have been validated against and found in good agreement with the measured results of the only reported satellite‐to‐ground QKD experiments till date. The presented QBER modelling and analysis will aid in system engineering and efficient design of future satellite‐based QKD systems.

Abstract We conducted a pre‐post intervention study to determine knowledge, attitude, and practice toward dietary salt intake before, immediately, and 1‐month after nurse‐led one‐on‐one counseling. We purposively selected three public health facilities in Agra, India, and enrolled all eligible hypertensive patients aged 18–60 under treatment for ≥6 months. Of the 153 patients at the 1‐month follow‐up, counseling improved knowledge (4% vs. 42%, p

Abstract In vertebrates, many organs, such as the kidney and the mammary gland form ductal structures based on the folding of epithelial sheets. The development of these organs relies on coordinated sorting of different cell lineages in both time and space, through mechanisms that remain largely unclear. Tissues are composed of several cell types with distinct biomechanical properties, particularly at cell‐cell and cell‐substrate boundaries. One hypothesis is that adjacent epithelial layers work in a coordinated manner to shape the tissue. Using in vitro experiments on model epithelial cells, differential expression of atypical Protein Kinase C iota (aPKCi), a key junctional polarity protein, is shown to reinforce cell epithelialization and trigger sorting by tuning cell mechanical properties at the tissue level. In a broader perspective, it is shown that in a heterogeneous epithelial monolayer, in which cell sorting occurs, forces arising from epithelial cell growth under confinement by surrounding cells with different biomechanical properties are sufficient to promote collective cell extrusion and generate emerging 3D organization related to spheroids and buds. Overall, this research sheds light on the role of aPKCi and the biomechanical interplay between distinct epithelial cell lineages in shaping tissue organization, providing insights into the understanding of tissue and organ development.

Background Chest pain (CP) in patients with nonobstructive coronary artery disease is a therapeutic challenge affecting morbidity and mortality. We aimed to identify clinical factors associated with CP in this population, hypothesizing that obesity and depressive symptoms are associated with CP. Methods and Results In 814 patients with angiographically confirmed nonobstructive coronary artery disease, we measured sociodemographic variables, clinical risk factors, medications, and Patient Health Questionnaire 9 scores for depressive symptoms. We assessed CP frequency and prevalence by using all items from the Seattle Angina Questionnaire angina frequency domain to generate an angina frequency composite score. In the overall sample (58.8±11.7 years old, 52.6% female), 42.8% had obesity, and 71.5% had CP, with an angina frequency composite score (SD) score of 76.4 (22.1). Compared with individuals without obesity, individuals with obesity had a higher prevalence (77.6% versus 67%, P

Key Clinical Message Stone heart syndrome has a complex interaction with digoxin toxicity, where, theoretically, the administration of intravenous calcium can worsen a patient's condition. Research on this subject is conflicting, so it is imperative to approach it cautiously.

ABSTRACT Background Sodium‐glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with or without Type 2 diabetes and heart failure (HF). However, studies have shown conflicting evidence regarding their efficacy in patients following acute myocardial infarction (MI). We conducted a pilot systematic review and meta‐analysis to synthesise the available evidence regarding the effectiveness of SGLT2 inhibitors in MI. Methods A systematic literature search was conducted using PubMed/MEDLINE, the Cochrane Library and Embase databases to identify randomised controlled trials (RCTs) that compared clinical outcomes of SGLT2 inhibitors with placebo following MI. We conducted the statistical analysis using RevMan, version 5.4 and pooled risk ratios (RRs) along the corresponding 95% confidence interval (CI) for all outcomes. Results Five RCTs reporting data for 11,211 patients were included in our study. The mean follow‐up duration was 43.8 weeks. Our pooled analysis showed that SGLT2 inhibitors significantly reduced the risk of hospitalisations for heart failure (HHF) (RR = 0.76, 95% CI: 0.61–0.88, p = 0.001) in patients with MI. However, the risk of all‐cause mortality (RR = 1.05, 95% CI: 0.78–1.41, p = 0.76), CV mortality (RR = 1.04, 95% CI = 0.84–1.29, p = 0.73) and all‐cause hospitalisations (RR = 1.06, 95% CI: 0.96–1.17, p = 0.25) remained comparable across the two groups. Conclusion SGLT2 inhibitors reduce HHF without affecting all‐cause mortality, CV mortality and all‐cause hospitalisations. However, further evidence is required to reach a definitive conclusion.

Abstract Background Obesity poses a significant global health challenge, necessitating effective prevention and treatment strategies. Exercise and diet are recognized as pivotal interventions in combating obesity. This study reviews the literature concerning the impact of exercise‐induced cytokines, dietary factors, and inflammation on adipose tissue metabolism, shedding light on potential pathways for therapeutic intervention. Methodology A comprehensive review of relevant literature was conducted to elucidate the role of exercise‐induced cytokines, including interleukin‐6 (IL‐6), interleukin‐15 (IL‐15), brain‐derived neurotrophic factor (BDNF), irisin, myostatin, fibroblast growth factor 21 (FGF21), follistatin (FST), and angiopoietin‐like 4 (ANGPTL4), in adipose tissue metabolism. Various databases were systematically searched using predefined search terms to identify relevant studies. Articles selected for inclusion underwent thorough analysis to extract pertinent data on the mechanisms underlying the influence of these cytokines on adipose tissue metabolism. Results and Discussion Exercise‐induced cytokines exert profound effects on adipose tissue metabolism, influencing energy expenditure (EE), thermogenesis, fat loss, and adipogenesis. For instance, IL‐6 activates AMP‐activated protein kinase (AMPK), promoting fatty acid oxidation and reducing lipogenesis. IL‐15 upregulates peroxisome proliferator‐activated receptor delta (PPARδ), stimulating fatty acid catabolism and suppressing lipogenesis. BDNF enhances AMPK‐dependent fat oxidation, while irisin induces the browning of white adipose tissue (WAT), augmenting thermogenesis. Moreover, myostatin, FGF21, FST, and ANGPTL4 each play distinct roles in modulating adipose tissue metabolism, impacting factors such as fatty acid oxidation, adipogenesis, and lipid uptake. The elucidation of these pathways offers valuable insights into the complex interplay between exercise, cytokines, and adipose tissue metabolism, thereby informing the development of targeted obesity management strategies. Conclusion Understanding the mechanisms by which exercise‐induced cytokines regulate adipose tissue metabolism is critical for devising effective obesity prevention and treatment modalities. Harnessing the therapeutic potential of exercise‐induced cytokines, in conjunction with dietary interventions, holds promise for mitigating the global burden of obesity. Further research is warranted to delineate the precise mechanisms underlying the interactions between exercise, cytokines, and adipose tissue metabolism.

Abstract Primary renal involvement by T lymphoblasts is rare among adults with T acute lymphoblastic leukaemia. We report a 28‐year‐old man presenting with acute renal failure due to infiltration by T lymphoblasts and his response to paediatric‐inspired modified BFM‐90 protocol. The patient achieved an initial complete remission (CR) but developed central nervous system relapse. He achieved CR2 with cranial irradiation and intrathecal chemotherapy. He underwent a haploidentical transplant in CR2 and remains in remission post‐transplant day 330. An early kidney biopsy helped confirm the diagnosis. Such presentations remain responsive to modified BFM‐90. An early allotransplant in CR2 remains the standard of care.

Abstract Background and Aim Celiac disease (CeD) is mainly reported from the northern and western parts of India. In central India, it is believed to be a disease of children, with limited data among adults diagnosed for the first time after the age of 18 years. Hence, we aimed to describe CeD's clinical and demographic features among adults and children/adolescents in central India. Methods This is a retrospective analysis of a prospectively maintained database of all patients diagnosed for CeD from 2010 to 2019. The disease in adults was confirmed when symptoms developed for the first time after 18 years and had positive anti‐transglutaminase antibodies with villous atrophy on duodenal biopsy. It was compared with pediatric patients with CeD diagnosed during the same time period. Results Of the 170 patients diagnosed with CeD, 118 were adults and 52 were children or adolescents. The mean age of presentation of adult CeD was 37.3 ± 11.93 years, while in the pediatric and adolescent group it was 9.19 ± 5.4 years. Classical presentation with chronic, painless, small‐bowel‐type diarrhea was seen in 44.1% of adults compared to 57.7% in the pediatric age group. Among the adult patients, 55.9% presented with nonclassical symptoms, which included abdominal pain (40.7%) and weight loss (36.4%). The common presenting symptom in children other than diarrhea was weight loss (50%) and abdominal pain (34.6%). Conclusion CeD is common in central India, with an increasing number of patients being diagnosed for the first time after 18 years of age and presenting more often with nonclassical symptoms.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by inflammatory assaults on the central nervous system (CNS), particularly on the optic nerves and spinal cord. In recent years, a wider range of clinical manifestations of this complex disease have been observed, emphasizing the importance of gaining a more profound understanding beyond optic neuritis (ON) and transverse myelitis (TM). Current knowledge This study explores the many clinical symptoms of NMOSD, including common and uncommon presentations. Distinctive aspects of ON, TM, and diencephalic/brainstem syndromes are examined, highlighting their unique characteristics in contrast to conditions such as multiple sclerosis. We also discuss extra‐CNS involvement, such as unusual signs, including muscle involvement, retinal injury, auditory impairment, and rhinological symptoms. Aims and objectives Our study intends to highlight the wide range and complexity of NMOSD presentations, emphasizing the significance of identifying unusual symptoms for precise diagnosis and prompt management. The specific processes that contribute to the varied clinical presentation of NMOSD are not well understood despite existing information. This emphasizes the necessity for more study to clarify the mechanisms that cause different symptoms and discover new treatment targets for this complex autoimmune disorder. Conclusion It is essential to acknowledge the complex and varied clinical manifestations of NMOSD to enhance diagnosis, treatment, and patient results. By enhancing our comprehension of the fundamental processes and investigating innovative therapeutic approaches, we may aim to enhance the quality of life for persons impacted by this illness.

Abstract The clinical translation of induced pluripotent stem cells (iPSCs) holds great potential for personalized therapeutics. However, one of the main obstacles is that the current workflow to generate iPSCs is expensive, time‐consuming, and requires standardization. A simplified and cost‐effective microfluidic approach is presented for reprogramming fibroblasts into iPSCs and their subsequent differentiation into neural stem cells (NSCs). This method exploits microphysiological technology, providing a 100‐fold reduction in reagents for reprogramming and a ninefold reduction in number of input cells. The iPSCs generated from microfluidic reprogramming of fibroblasts show upregulation of pluripotency markers and downregulation of fibroblast markers, on par with those reprogrammed in standard well‐conditions. The NSCs differentiated in microfluidic chips show upregulation of neuroectodermal markers (ZIC1, PAX6, SOX1), highlighting their propensity for nervous system development. Cells obtained on conventional well plates and microfluidic chips are compared for reprogramming and neural induction by bulk RNA sequencing. Pathway enrichment analysis of NSCs from chip showed neural stem cell development enrichment and boosted commitment to neural stem cell lineage in initial phases of neural induction, attributed to a confined environment in a microfluidic chip. This method provides a cost‐effective pipeline to reprogram and differentiate iPSCs for therapeutics compliant with current good manufacturing practices.

Key Clinical Message Pericardial sarcoidosis is an uncommon cause of chest pain to consider, and it requires a heightened level of suspicion and thorough history gathering. If there is suspicion of inflammatory disease, pursuing advanced imaging and biopsies is crucial, as early immunosuppressive treatment can enhance outcomes. Abstract Pericardial involvement in sarcoidosis is a rare condition with limited research. This case study discusses a 52‐year‐old African American woman who presented with subacute chest pain and was diagnosed with pericardial sarcoidosis. Diagnostic evaluation revealed extensive lymphadenopathy and pericardial effusion, and a pericardial biopsy confirmed non‐caseating granulomatous inflammation. Treatment with steroids and methotrexate resulted in clinical improvement. Eight months follow‐up showed near resolution of pericardial disease. This case emphasizes the importance of considering cardiac sarcoidosis in sarcoidosis patients, utilizing advanced imaging for accurate diagnosis, and tailoring treatment to the level of cardiac involvement.

Abstract Gut microbiome dysbiosis is a major contributing factor to several pathological conditions. However, the mechanistic understanding of the communication between gut microbiota and extra‐intestinal organs remains largely elusive. Extracellular vesicles (EVs), secreted by almost every form of life, including bacteria, could play a critical role in this inter‐kingdom crosstalk and are the focus of present study. Here, we present a novel approach for isolating lipopolysaccharide (LPS)+ bacterial extracellular vesicles (bEVLPS) from complex biological samples, including faeces, plasma and the liver from lean and diet‐induced obese (DIO) mice. bEVLPS were extensively characterised using nanoparticle tracking analyses, immunogold labelling coupled with transmission electron microscopy, flow cytometry, super‐resolution microscopy and 16S sequencing. In liver tissues, the protein expressions of TLR4 and a few macrophage‐specific biomarkers were assessed by immunohistochemistry, and the gene expressions of inflammation‐related cytokines and their receptors (n = 89 genes) were measured using a PCR array. Faecal samples from DIO mice revealed a remarkably lower concentration of total EVs but a significantly higher percentage of LPS+ EVs. Interestingly, DIO faecal bEVLPS showed a higher abundance of Proteobacteria by 16S sequencing. Importantly, in DIO mice, a higher number of total EVs and bEVLPS consistently entered the hepatic portal vein and subsequently reached the liver, associated with increased expression of TLR4, macrophage markers (F4/80, CD86 and CD206), cytokines and receptors (Il1rn, Ccr1, Cxcl10, Il2rg and Ccr2). Furthermore, a portion of bEVLPS escaped liver and entered the peripheral circulation. In conclusion, bEV could be the key mediator orchestrating various well‐established biological effects induced by gut bacteria on distant organs.

Background There are limited data about the impact of timing of pulmonary valve replacement (PVR) on right heart reverse remodeling in patients with pulmonary regurgitation following intervention for isolated pulmonary valve stenosis (PS). This study compared differences in postprocedural right heart reverse remodeling after early versus late PVR (defined as PVR before versus after attainment of the conservative consensus criteria proposed by Bokma et al, 2018) in patients with prior intervention for PS, using patients with tetralogy of Fallot as the reference group. Method and Results Right atrial reservoir strain and right ventricular free wall strain was measured at baseline, 1 and 3 years after PVR. There were 114 patients with PS (early PVR, 87 [76%]; late PVR, 27 [24%]) and 291 patients with tetralogy of Fallot (early PVR, 197 [67%]; late PVR, 96 [33%]). The PS group had greater improvement in right atrial reservoir strain at 1 year (12%±4% versus 8%±4%; P

Background The long‐term impact of weight gain (WG) on cardiovascular outcomes among patients with atrial fibrillation (AF) is unclear. Methods and Results We studied 62 871 (mean age, 72±12, 43% women) adult patients with AF evaluated at the University of Pittsburgh Medical Center between January 1, 2010, and May 13, 2021. Serial body mass index, risk factors, comorbidities, and subsequent death and hospitalization were ascertained and stratified according to percentage WG (≥0% to

Abstract Objectives To describe findings from an otolaryngology‐specific needs assessment tool in Zimbabwe. Methods Surveys were developed and shared with Low‐Middle Income Country (LMIC) hosting institutions in Zimbabwe and to High‐Income Country surgical trip participants (HIC). Respondents were otolaryngologists identified online and through professional networks who had participated in a surgical trip. Results The most common procedures Zimbabwe otolaryngologists reported treating were adenotonsillectomy (85.7%), chronic rhinosinusitis (71.4%), chronic otitis (57.1%), and head and neck tumor intervention (57.1%). The most common untreatable conditions that host physicians wanted to treat were skull base surgery (71.4%), flap reconstructions (57.1%), and laryngotracheal reconstruction (57.1%). The largest discrepancy between host desires and visiting team offerings were flap reconstruction (57.1%), nasal bone deformities (37.1%), and laryngotracheal reconstruction (17.1%). Perceptions of short‐term surgical trips (STST) were recorded for host and visiting teams, and important differences between the public and private sectors of care in Zimbabwe were also identified. Conclusion The surveys utilized in this study served as a bidirectional needs assessment of the requirements and care goals of host institutions and visiting teams in Zimbabwe. Differences between public and private sectors of care, particularly regarding infrastructure, resources, and surgical goals, were revealed, and the results can be utilized as part of efforts to maximize efforts within global surgical partnerships. Level of Evidence VI.

Abstract A trilateral control for LCL filter‐based system is introduced by the authors with a single grid current sensor in weak grid conditions. The LCL filter increases the complexity when the uncertain nature of the grid comes into the picture. Moreover, the traditional three‐loop control technique requires three current sensors on the inverter side, three voltage sensors to sense voltage across the capacitor, and three current sensors on the grid side combined for sensing. A novel trilateral control technique utilising a single sensor is implemented to sense the grid current. This technique has reduced a considerable number of current sensors and voltage sensors. The α axis of grid current is proportional to sensed ‘a’ phase grid current. The β current in the utility grid is acquired by employing the controller reference quantities of the grid current. The computation of another variable, that is, the current in the inverter side inductor and the voltage across the capacitor, is executed by an estimation algorithm. The proposed technique provides the feature of reducing implementation financial value and weight that reduces the complexity and size of hardware. The synchronisation technique is executed by a modified dual second‐order generalised integrator digital phase‐locked loop for the grid‐connected converter. The implemented system offers the advantage of ease of implementation, good performance, and high stability. The validity of the proposed scheme in the implemented system is demonstrated by the simulated waveform obtained on the MATLAB/Simulink platform. Finally, the effectiveness of the proposed system is further justified by the experimental waveform procured from a prototype developed in the laboratory.

Abstract Objective To compare the renal artery (RA) flow indices (RI and PI) among normohydramnios, idiopathic oligohydramnios, and polyhydramnios and determine applicability of fetal RA Doppler indices in predicting the pregnancy outcome. Methods Total 106 3rd trimester pregnant patients were divided into cases and controls based on amniotic fluid index. Routine antenatal and color Doppler (including kidneys) ultrasound was performed for all patients in this study. The postnatal follow‐up was done, and the pregnancies having poor outcomes in terms of NICU admissions were assessed. Results Statistically significant differences were noted when comparing RI and PI values of normohydramnios (0.91 ± 0.04 and 2.38 ± 0.21, respectively) with oligohydramnios (1.02 ± 0.07 and 2.99 ± 0.38, respectively) and polyhydramnios (0.90 ± 0.12 and 2.7 ± 0.84, respectively) independently (p value

Abstract Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward.

Evidence from medicine and other fields has shown that gender diversity results in better decision making and outcomes. The incoming workforce of congenital heart specialists (especially in pediatric cardiology) appears to be more gender balanced, but past studies have shown many inequities. Gender‐associated differences in leadership positions, opportunities presented for academic advancement, and recognition for academic contributions to the field persist. In addition, compensation packages remain disparate if evaluated based on gender with equivalent experience and expertise. This review explores these inequities and has suggested individual and institutional changes that could be made to recruit and retain women, monitor the climate of the institution, and identify and eliminate bias in areas like salary and promotions.

ABSTRACT Aims The once‐weekly insulin icodec, a new basal insulin analog, may positively support a reduction in injection frequency and improve adherence to therapy in type 2 diabetes (T2D). This study aimed to evaluate the safety and efficacy of insulin icodec compared with those of once‐daily glargine U100. Methods A comprehensive literature search was conducted using PubMed/MEDLINE, Embase and the Cochrane Library from inception till September 2023. Data about clinical outcomes in both groups were extracted. Forest plots were generated using the random‐effects model by pooling odds ratios (ORs) and mean differences (MDs). Results Five randomised controlled trials and 2019 individuals with T2DM were included. In the pooled analysis, time in range was significantly higher (MD = 4.35; 95% CI: 1.65 to 7.05; p = 0.002) in the icodec group than in the once‐daily glargine group. The HbA1c levels were significantly reduced (MD = −0.13; 95% CI: −0.24 to −0.03; p = 0.02) in the weekly icodec group compared with those in the once‐daily glargine group. The weight gain was significantly less in the glargine group than in the weekly icodec group (MD = 0.41; 95% CI: 0.04 to 0.78; p = 0.03); however, in the subgroup analysis, this change became statistically insignificant in both insulin‐naïve and previously insulin‐treated individuals. The results were comparable across two groups for fasting plasma glucose levels, hypoglycaemia alert (Level 1), clinically significant (Level 2) or severe hypoglycaemia (Level 3), and adverse events. Conclusion Insulin icodec was associated with a reduction in glycated haemoglobin levels and higher time in range, with a similar safety profile as compared to insulin glargine U100. However, further evidence is still needed to reach a definitive conclusion.

Abstract Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS‐MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib‐based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression‐free survival (PFS) (hazard ratio [HR] = 2.77; p = 0.0047) and overall survival (OS) (HR = 2.9; p = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; p = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; p = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum‐immunofixation‐based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; p = 0.025) and OS (HR = 3.97; p = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS‐MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.

Abstract Nonalcoholic fatty liver disease affects 30% of the United States population and its progression can lead to nonalcoholic steatohepatitis (NASH), and increased risks for cirrhosis and hepatocellular carcinoma. NASH is characterized by a highly heterogeneous liver microenvironment created by the fibrotic activity of hepatic stellate cells (HSCs). While HSCs have been widely studied in 2D, further advancements in physiologically relevant 3D culture platforms for the in vitro modeling of these heterogeneous environments are needed. In this study, the use of stiffness‐variable, extracellular matrix (ECM) protein‐conjugated polyethylene glycol microgels as 3D cell culture scaffolds to modulate HSC activation is demonstrated. These microgels as a high throughput ECM screening system to identify HSC matrix remodeling and metabolic activities in distinct heterogeneous microenvironmental conditions are further employed. The 6 kPa fibronectin microgels are shown to significantly increase HSC matrix remodeling and metabolic activities in single or multiple‐component microenvironments. Overall, heterogeneous microenvironments consisting of multiple distinct ECM microgels promoted a decrease in HSC matrix remodeling and metabolic activities compared to homogeneous microenvironments. The study envisions this ECM screening platform being adapted to a broad number of cell types to aid the identification of ECM microenvironments that best recapitulate the desired phenotype, differentiation, or drug efficacy.

Abstract INTRODUCTION The variability in apolipoprotein E (APOE) ε4‐attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. METHODS We examined associations of compound genotypes (CompGs) comprising the ε4‐encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD‐affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. RESULTS The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4‐bearing CompGs define lower‐ and higher‐AD‐risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear—with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between—patterns across ages. DISCUSSION The ε4‐bearing CompGs have a potential to differentiate biological mechanisms of sex‐, age‐, and ancestry‐specific AD risks and serve as AD biomarkers. Highlights Younger White women carrying the lower‐risk (LR) CompG are at small risk of AD. Black carriers of the LR CompG are at negligible risk of AD at 85 years and older. The higher‐risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years. AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs. Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.

Key Clinical Message We report an unusual case presentation of a patient with necrotic tissue changes of the right second and third fingers, found to have myeloid sarcoma with Staphylococcus‐positive tenosynovitis and underlying acute myeloid leukemia, to highlight the importance of comprehensive evaluation in patients with atypical wounds.

Abstract Objectives The incidence of young‐onset oral squamous cell carcinoma (OSCC) is growing, even among non‐smokers/drinkers. The effects of adverse histopathological features on long‐term oncologic outcomes between the young and old are controversial and confounded by significant heterogeneity. Few studies have evaluated the socio‐economic impact of premature mortality from OSCC. Our study seeks to quantify these differences and their economic impact on society. Materials and Methods Four hundred and seventy‐eight young (

Abstract Introduction Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family‐centred care need information about the characteristics of existing interventions, their development and the domains of family‐centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family‐centred interventions designed to improve experiences with care for children with chronic conditions. Methods We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7–20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family‐centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full‐text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family‐centred care. Results Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed‐methods studies (n = 9 each). The most frequently addressed domains of family‐centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). Conclusion This review, which identified 61 unique interventions aimed at improving family‐centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high‐needs population. Patient or Public Contribution This study was co‐developed with three patient partner co‐investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co‐investigators contributed to this study at all stages, from conceptualization to dissemination.

Background In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. Methods and Results In the ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow‐up: 26.2 months; interquartile range: 19.0–34.9 months). Median age was 67.6 years (interquartile range: 60.7–73.6 years). Among participants aged 0.05 for all). Conclusions Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

Background Left ventricular dysfunction is characterized by systolic and diastolic parameters, leading to heart failure (HF) with reduced or preserved ejection fraction (EF), respectively. The goal of this study is to examine the impact of left ventricular systolic and diastolic dysfunction (DD) on patient outcomes. Methods and Results Two cohorts were used in this analysis: Cohort A included 136 455 patients with EF ≥50%, stratified by the presence and grade of DD. Cohort B included 16 850 patients with EF

Abstract The spatial and temporal distribution of Alpine snow is a sensitive gauge of environmental change. While understanding past snow dynamics is essential for reconstructing past climate and forecasting future trends, reliable snowpack data prior to the instrumental record are scarce. We present a novel pairing of cosmogenic paleothermometry and luminescence photochronometry which constrain the temperature and insolation history of bedrock outcrops at the Gotthard Pass, Switzerland, over the last ∼15,000 years. By coupling these results with cosmogenic 14C‐10Be chronology and modern in situ rock thermometry, we infer a ∼70‐day reduction of snowpack at the topographic mid‐slope. Our data indicate stable environmental conditions throughout the Holocene, followed by a 6.6 ± 2.9°C increase of ground surface temperature, coeval with an order‐of‐magnitude or more increase in ground surface insolation. Bracketing the onset of these changes between 1504 and 1807 CE, our findings tie the snowpack decline with the onset of human industrialization.

Background Little is known about outcomes following heart failure (HF) hospitalization among adults with congenital heart disease (CHD) in the United States. We aim to compare the outcomes of HF versus non‐HF hospitalizations in adults with CHD. Methods and Results Using a national deidentified administrative claims data set, patients with adult congenital heart disease (ACHD) hospitalized with and without HF (ACHDHF+, ACHDHF−) were characterized to determine the predictors of 90‐day and 1‐year mortality and quantify the risk of mortality, major adverse cardiac and cerebrovascular events, and health resource use. Cox proportional hazard regression was used to compare ACHDHF+ versus ACHDHF− for risk of events and health resource use. Of 26 454 unique ACHD admissions between January 1, 2010 and December 31, 2020, 5826 (22%) were ACHDHF+ and 20 628 (78%) were ACHDHF−. The ACHD HF+ hospitalizations increased from 6.6% to 14.0% (P

Background Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance—isolated postcapillary PH (IpcPH) and combined pre‐ and postcapillary PH (CpcPH), respectively—has been incompletely defined using unbiased methods. Methods and Results Patients with extremes of IpcPH versus CpcPH were identified from a single‐center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction

Abstract Projections of future carbon sinks and stocks are important because they show how the world's ecosystems will respond to elevated CO2 and changes in climate. Moreover, they are crucial to inform policy decisions around emissions reductions to stay within the global warming levels identified by the Paris Agreement. However, Earth System Models from the 6th Coupled Model Intercomparison Project (CMIP6) show substantial spread in future projections—especially of the terrestrial carbon cycle, leading to a large uncertainty in our knowledge of any remaining carbon budget (RCB). Here we evaluate the global terrestrial carbon cycle projections on a region‐by‐region basis and compare the global models with regional assessments made by the REgional Carbon Cycle Assessment and Processes, Phase 2 activity. Results show that for each region, the CMIP6 multi‐model mean is generally consistent with the regional assessment, but substantial cross‐model spread exists. Nonetheless, all models perform well in some regions and no region is without some well performing models. This gives confidence that the CMIP6 models can be used to look at future changes in carbon stocks on a regional basis with appropriate model assessment and benchmarking. We find that most regions of the world remain cumulative net sources of CO2 between now and 2100 when considering the balance of fossil‐fuels and natural sinks, even under aggressive mitigation scenarios. This paper identifies strengths and weaknesses for each model in terms of its performance over a particular region including how process representation might impact those results and sets the agenda for applying stricter constraints at regional scales to reduce the uncertainty in global projections.

Background Literature suggests a bidirectional association between advanced hepatic fibrosis (AHF) and coronary artery disease (CAD). We evaluated the association of AHF with immune activation, systemic inflammation, and adverse outcomes in patients with CAD. Methods and Results A fibrosis‐4 index cutoff value ≥2.67 was used to define AHF. Circulating levels of soluble urokinase plasminogen activator receptor and hsCRP (high‐sensitivity C‐reactive protein) were measured as markers for immune activation and systemic inflammation, respectively. The relationship of AHF with soluble urokinase plasminogen activator receptor, hsCRP, and adverse cardiovascular outcomes was evaluated. Among 3406 participants with CAD, 479 had AHF. Participants with AHF were older; were less likely to be Black individuals; and had a lower body mass index, worse renal function, and a prior history of heart failure. In multivariable linear regression models adjusted for clinical and demographic confounders, participants with AHF had 15.6% higher soluble urokinase plasminogen activator receptor and 24.0% higher hsCRP levels. They were more likely to experience the following adverse outcomes: all‐cause death (adjusted hazard ratio [HR], 1.57 ([95% CI, 1.29–1.92]; P

Abstract Discrete aurora are sporadic emissions of light originating in Mars upper atmosphere. We report nadir imaging observations from MAVEN's Imaging UltraViolet Spectrograph which identify the conditions which trigger electron precipitation causing these events. Prior studies have shown that discrete aurora events in the strong crustal magnetic field region in the southern hemisphere are the brightest and most repeatable compared to events occurring outside the region. Our new data set offers a more complete and accurate characterization of aurora in this area. The region of strongest crustal fields is composed of two distinct magnetic regions, with magnetic fields in opposite directions; discrete aurora events trigger in one region after dusk and in the other before dawn. Magnetic reconnection in these two adjacent regions with the draped interplanetary field may open the crustal fields in these regions during opposing local times. Particle precipitation can then cause discrete aurora at the observed times and locations.

Abstract Background Water T2 (T2H2O) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. Methods Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3‐tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. Results A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6‐min walk than those with a lower T2H2O (

Abstract Background Prebiotics is a relatively neglected area in cancer research, despite evidence suggesting that it plays a key role in suppressing tumour growth and improving immune function. Recent Findings Including prebiotics in the diet has been shown to strengthen the immune system and can better slow down or prevent the growth of tumours. It has also been strongly indicated in various scientific studies that prebiotics can contribute to the sustenance of a healthy microbiome, which in turn plays an important role in increasing the effectiveness and reducing the side effects of cancer treatments. Conclusion In the present review article we highlight the mechanisms by which prebiotics like inulin, fructooligosaccharide (FOS), β‐glucan, pectin, and xylooligosaccharide (XOS) function. Furthermore, the beneficial effect of incorporating prebiotics during cancer therapy to improvise gut health and prevent/reverse the damage caused to patients due to chemotherapy has also been elaborated.

Abstract Since every biological system requires capillaries to support its oxygenation, design of engineered preclinical models of such systems, for example, vascularized microphysiological systems (vMPS) have gained attention enhancing the physiological relevance of human biology and therapies. But the physiology and function of formed vessels in the vMPS is currently assessed by non‐standardized, user‐dependent, and simple morphological metrics that poorly relate to the fundamental function of oxygenation of organs. Here, a chained neural network is engineered and trained using morphological metrics derived from a diverse set of vMPS representing random combinations of factors that influence the vascular network architecture of a tissue. This machine‐learned algorithm outputs a singular measure, termed as vascular network quality index (VNQI). Cross‐correlation of morphological metrics and VNQI against measured oxygen levels within vMPS revealed that VNQI correlated the most with oxygen measurements. VNQI is sensitive to the determinants of vascular networks and it consistently correlates better to the measured oxygen than morphological metrics alone. Finally, the VNQI is positively associated with the functional outcomes of cell transplantation therapies, shown in the vascularized islet‐chip challenged with hypoxia. Therefore, adoption of this tool will amplify the predictions and enable standardization of organ‐chips, transplant models, and other cell biosystems.

Key Clinical Message It is important to consider WDLS as a potential cause of tongue lesions and include it in the list of differential diagnoses. When performing surgical intervention, it is crucial to remove enough tissue around the lesion, and regular follow‐up is necessary due to the high risk of recurrence, despite its rarity, when margins are positive. Abstract Liposarcoma (LS) is the most common soft tissue sarcomas (STSs) that arise from embryonic mesenchymal tissue. Though these sarcomas commonly arise at retroperitoneal locations and extremities, the appearance of these tumors in the head and neck region is rare, with the tongue as a preferred site. As per WHO 2020, LS is classified into four subtypes based on morphology, namely, Well‐differentiated liposarcoma (WDLS), Dedifferentiated liposarcoma (DDLS), Myxoid liposarcoma (MLS), and Pleomorphic liposarcoma (PLS). WLS is the most common variant among all. Here, we had a case of 55 years old male with the complaint of swelling in the left lateral border of the tongue with the preliminary diagnosis of pleomorphic adenoma. The patient underwent a left partial glossectomy with adequate margins. Further evaluation of the lesion revealed a clear cell tumor that was ultimately confirmed as liposarcoma on immunohistochemistry that showed tumor cells positive for S100, CDK4, and MDM2 with 2% Ki‐67. Postsurgical status of the patient was evaluated by F18 FDG PET CTscan, which was normal. Currently, the patient is under regular follow‐up.

Background The survival benefit of revascularization of chronic total occlusion (CTO) of the coronary arteries remains a subject of controversy. We measured high sensitivity troponin‐I (hsTn‐I) levels as an estimate of myocardial ischemia in patients with stable coronary artery disease, with the hypothesis that (1) patients with CTO have higher levels of hsTn‐I than patients without CTO, (2) hsTn‐I levels will predict adverse cardiovascular events in patients with CTO, and (3) patients with elevated hsTn‐I levels will have a survival benefit from CTO revascularization. Methods and Results In 428 patients with stable coronary artery disease and CTO undergoing coronary angiography, adverse event rates were investigated. Cox proportional hazards models and Fine and Gray subdistribution hazard models were performed to determine the association between hsTn‐I level and incident event rates in patients with CTO. HsTn‐I levels were higher in patients with compared with those without CTO (median 6.7 versus 5.6 ng/L, P=0.002). An elevated hsTn‐I level was associated with higher adverse event rates (adjusted all‐cause mortality hazard ratio, 1.19 [95% CI, 1.08–1.32]; P=0.030) for every doubling of hsTn‐I level. CTO revascularization was performed in 28.3% of patients. In patients with a high (>median) hsTn‐I level, CTO revascularization was associated with substantially lower all‐cause mortality (adjusted hazard ratio, 0.26 [95% CI, 0.08–0.88]; P=0.030) compared with those who did not undergo revascularization. In patients with a low (

Background The ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high‐ versus low‐dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non‐P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22–1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91–2.22]). We found no interaction in the relative effectiveness and safety of high‐ versus low‐dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high‐dose compared with low‐dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high‐ versus low‐dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.