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Background Minor events that occur in the workplace sometimes are evaluated with MRI, which may reveal age-related changes in the symptomatic body part. These age-related changes are often ascribed to the event. However, evidence of similar or worse pathophysiology in the contralateral joint would suggest that the symptoms might be new, but the pathophysiology is not. Questions/purposes Using a convenience sample of occupational injury claimants with bilateral MRI to evaluate unilateral knee or shoulder symptoms ascribed to a single event at work, we sought to determine whether MRI findings of the shoulder and knee are more often congruent or incongruent with new unilateral symptoms. Methods Two hundred ninety-four occupational injury claimants employed at companies throughout Texas that do not subscribe to workers’ compensation insurance, who were older than 40 years, and with unilateral shoulder or knee symptoms, were studied. Starting in 2012, all patients seen by OccMD Group PA who present with unilateral symptoms ascribed to work undergo bilateral MRI, based on several previous occasions where bilateral MRI proved to be a compelling demonstration that perceived injuries are more likely age-related, previously well-adapted pathophysiology. MRI findings (anything described as abnormal by the radiologist; eg, defect size or signal change) was considered congruent if the abnormality of one or more structures on the symptomatic side was greater than that of the corresponding structures in the asymptomatic joint. Bivariate analysis was used to compare the frequency of MRI findings congruent and incongruent with symptoms. Logistic regression was used to evaluate factors associated with MRI findings of the shoulder or knee. Results Less than half of the patients with shoulder (90 of 189; 48%; p = 0.36) or knee (45 of 105; 43%; p = 0.038) symptoms had worse pathologic features on the symptomatic side. Older age was associated with disorders in the infraspinatus tendon (59 ± 8 versus 56 ± 8 years; p = 0.012), glenoid labrum (60 ± 9 versus 57 ± 8 years; p = 0.025), and biceps tendon (60 ± 8 versus 57 ± 8 years; p = 0.0038). Eighty-seven percent of patients (91 of 105) had structural changes in the medial meniscus described by the radiologist. Conclusions Occupational injury claimants 40 years of age and older with unilateral knee and shoulder symptoms ascribed to a work event tend to have bilateral age-related MRI changes. Age-related disorders should be distinguished from acute injury. Level of Evidence Level IV, diagnostic study.

In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed ‘fibromyocytes’, rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21—a causal CAD gene—markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.

Data privacy mechanisms are essential for rapidly scaling medical training databases to capture the heterogeneity of patient data distributions toward robust and generalizable machine learning systems. In the current COVID-19 pandemic, a major focus of artificial intelligence (AI) is interpreting chest CT, which can be readily used in the assessment and management of the disease. This paper demonstrates the feasibility of a federated learning method for detecting COVID-19 related CT abnormalities with external validation on patients from a multinational study. We recruited 132 patients from seven multinational different centers, with three internal hospitals from Hong Kong for training and testing, and four external, independent datasets from Mainland China and Germany, for validating model generalizability. We also conducted case studies on longitudinal scans for automated estimation of lesion burden for hospitalized COVID-19 patients. We explore the federated learning algorithms to develop a privacy-preserving AI model for COVID-19 medical image diagnosis with good generalization capability on unseen multinational datasets. Federated learning could provide an effective mechanism during pandemics to rapidly develop clinically useful AI across institutions and countries overcoming the burden of central aggregation of large amounts of sensitive data.

2014 marked the sixth and most widespread mass bleaching event reported in the Northwestern Hawaiian Islands, home to the Papahānaumokuākea Marine National Monument (PMNM), the world's second largest marine reserve. This event was associated with an unusual basin-scale warming in the North Pacific Ocean, with an unprecedented peak intensity of around 20°C-weeks of cumulative heat stress at Lisianksi Island. In situ bleaching surveys and satellite data were used to evaluate the relative importance of potential drivers of bleaching patterns in 2014, assess the subsequent morality and its effects on coral communities and 3D complexity, test for signs of regional acclimation, and investigate long-term change in heat stress in PMNM. Surveys conducted at four island/atoll (French Frigate Shoals, Lisianski Island, Pearl and Hermes Atoll, and Midway Atoll) showed that in 2014, percent bleaching varied considerably between islands/atolls and habitats (back reef/fore reef and depth), and was up to 91% in shallow habitats at Lisianski. The percent bleaching during the 2014 event was best explained by a combination of duration of heat stress measured by Coral Reef Watch's satellite Degree Heating Week, relative community susceptibility (bleaching susceptibility score of each taxon * the taxon's abundance relative to the total number of colonies), depth and region. Mean coral cover at permanent Lisianski monitoring sites decreased by 68% due to severe losses of Montipora dilatata complex, resulting in rapid reductions in habitat complexity. Spatial distribution of the 2014 bleaching was significantly different from the 2002 and 2004 bleaching events likely due to a combination of differences in heat stress and local acclimatization. Historical satellite data demonstrated heat stress in 2014 was unlike any previous event and that the exposure of corals to the bleaching-level heat stress has increased significantly in the northern PMNM since 1982, highlighting the increasing threat of climate change to reefs.

Background Psoriasis impacts 1–3% of the world’s population and is characterized by hyper-proliferation of keratinocytes and increased inflammation. At the molecular level, psoriasis is commonly driven by a Th17 response, which serves as a major therapeutic target. Microbiome perturbations have been associated with several immune-mediated diseases such as atopic dermatitis, asthma, and multiple sclerosis. Although a few studies have investigated the association between the skin microbiome and psoriasis, conflicting results have been reported plausibly due to the lack of standardized sampling and profiling protocols, or to inherent microbial variability across human subjects and underpowered studies. To better understand the link between the cutaneous microbiota and psoriasis, we conducted an analysis of skin bacterial communities of 28 psoriasis patients and 26 healthy subjects, sampled at six body sites using a standardized protocol and higher sequencing depth compared to previous studies. Mouse studies were employed to examine dermal microbial-immune interactions of bacterial species identified from our study. Results Skin microbiome profiling based on sequencing the 16S rRNA V1–V3 variable region revealed significant differences between the psoriasis-associated and healthy skin microbiota. Comparing the overall community structures, psoriasis-associated microbiota displayed higher diversity and more heterogeneity compared to healthy skin bacterial communities. Specific microbial signatures were associated with psoriatic lesional, psoriatic non-lesional, and healthy skin. Specifically, relative enrichment of Staphylococcus aureus was strongly associated with both lesional and non-lesional psoriatic skin. In contrast, Staphylococcus epidermidis and Propionibacterium acnes were underrepresented in psoriatic lesions compared to healthy skin, especially on the arm, gluteal fold, and trunk. Employing a mouse model to further study the impact of cutaneous Staphylcoccus species on the skin T cell differentiation, we found that newborn mice colonized with Staphylococcus aureus demonstrated strong Th17 polarization, whereas mice colonized with Staphylococcus epidermidis or un-colonized controls showed no such response. Conclusion Our results suggest that microbial communities on psoriatic skin is substantially different from those on healthy skin. The psoriatic skin microbiome has increased diversity and reduced stability compared to the healthy skin microbiome. The loss of community stability and decrease in immunoregulatory bacteria such as Staphylococcus epidermidis and Propionibacterium acnes may lead to higher colonization with pathogens such as Staphylococcus aureus , which could exacerbate cutaneous inflammation along the Th17 axis.

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling—a hallmark and key driver of PDAC—is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular “AND-gate” such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2 . Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.

George Kunos and his colleagues show in a rat model that endocannabinoid activation of the Nlrp3 inflammasome in macrophages results in death of pancreatic beta cells, and thus development of type 2 diabetes mellitus. These results suggest that preventing this process might be a therapeutic option for diabetes in the clinic. Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB 1 receptors (CB 1 Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB 1 R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB 1 R-deficient ( Cnr1 −/− ) or Nlrp3 −/− mice, with the endocannabinoid anandamide. Peripheral CB 1 R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB 1 R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB 1 R as a therapeutic target in T2DM.