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Background Current guidelines recommend transcatheter aortic valve implantation (TAVI) for patients with aortic stenosis and porcelain aorta (PA). Neurological outcomes of patients with PA undergoing TAVI with modern valves require clarification as most trials examined balloon-expandable valves (BEV) and self-expandable valves in intermediate or high-risk patients, but not specifically in patients with PA. Our aim was to compare outcomes, including stroke and mortality, in well-matched patients with and without PA who received BEV during transfemoral TAVI procedures.Methods Consecutive patients undergoing TAVI were entered into a registry. For this single-centre (Zentralklinik Bad Berka, Germany), retrospective analysis, we only selected patients who received BEV. PA diagnosis was made when non-contrast axial CT images fulfilled Valve Academic Research Consortium-2 criteria for PA. There was 2:1 nearest neighbour matching of patients without and with PA. The primary outcome measure was 30-day mortality or stroke within 72 hours. Secondary outcome measures were 30-day mortality, stroke within 72 hours, technical success and 30-day device success.Results After matching patients with (n=141) and without PA (n=282), the primary outcome of mortality at

Peripheral nerve injury (PNI) is characterized by a loss of cellular and axonal integrity, often leading to limited functional recovery and pain. Many PNIs are not amenable to repair with traditional techniques; however, cell therapies, particularly Schwann cells (SCs), offer the promise of neural tissue replacement and functional improvement. Exosomes, which carry cellular signaling molecules, can be secreted by SCs and have shown promise in PNI. Our laboratory has had success using SCs in preclinical and clinical treatment settings. Transplanted cells have several known limitations, which exosomes mitigate. To that end, the current study investigated if implanted SC-derived exosomes in conduits, conduits with SCs, reverse autograft, or empty conduits comparably improve axonal regeneration and pain outcomes 16-weeks after repair of a long gap PNI in adult rats. Results show that there were no differences between groups in the von Frey filament testing or in the Hargreaves test. Electrophysiological testing showed a significant difference between the injured (ipsilateral) and uninjured (contralateral) limbs while histological assessment showed a significant difference between axonal counts in different areas of the conduit. Based on the results of the current study, more research is needed to understand the therapeutic role of exosomes in PNI.

Abstract Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or not standardized. Here, we present the curatedPCaData R package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights. curatedPCaData is an open and accessible community resource with code made available for reproducibility.

Abstract Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.

Summary: Individuals with Down syndrome (DS) clinically manifest severe respiratory illnesses; however, there is a paucity of data on how DS influences homeostatic physiology of lung airway, and its reactive responses to pulmonary pathogens. We generated well-differentiated ciliated airway epithelia using tracheas from wild-type and Dp(16)1/Yey mice in vitro, and discovered that Dp(16)1/Yey epithelia have significantly lower abundance of ciliated cells, an altered ciliary beating profile, and reduced mucociliary transport. Interestingly, both sets of differentiated epithelia released similar quantities of viral particles after infection with influenza A virus (IAV). However, RNA-sequencing and proteomic analyses revealed an immune hyperreactive phenotype particularly for monocyte-recruiting chemokines in Dp(16)1/Yey epithelia. Importantly, when we challenged mice in vivo with IAV, we observed immune hyper-responsiveness in Dp(16)1/Yey mice, evidenced by higher quantities of lung airway infiltrated monocytes, and elevated levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid. Our findings illuminate mechanisms underlying DS-mediated pathophysiological changes in airway epithelium.

IntroductionPeripheral nerve injuries are common neurologic injuries that are challenging to treat with current therapies. Electrical stimulation has been shown to accelerate reinnervation and enhance functional recovery. This study aims to review the literature on clinical application of electrical stimulation for peripheral nerve injury.MethodsPubMed and Embase were sourced from 1995 to August 2022. Selection was based on predetermined inclusion/exclusion criteria. Eight hundred and thirty-five articles were screened with seven being included in this review.ResultsTwo hundred and twenty-nine patients with peripheral nerve injuries were represented. Six of the studies were randomized controlled trials. A variety of nerve injuries were represented with all being in the upper extremity and supraclavicular region. Electrical stimulation protocols and evaluation varied. Electrodes were implanted in four studies with one also implanting the stimulator. Length of stimulation per session was either 20 mins or 1 h. Median stimulation frequency was 20 Hz. Stimulation intensity varied from 3 to 30V; pulse width ranged from 0.1 to 1.007 ms. Three protocols were conducted immediately after surgery. Patients were followed for an average of 13.5 months and were evaluated using electrophysiology and combinations of motor, sensory, and functional criteria.DiscussionPatients who received electrical stimulation consistently demonstrated better recovery compared to their respective controls. Electrical stimulation for peripheral nerve injury is a novel treatment that has not been well-studied in humans. Our review illustrates the potential benefit in implementing this approach into everyday practice. Future research should aim to optimize protocol for clinical use.

Background: Nerve injury following arthroscopic shoulder procedures is a rare complication. Most patients will have gradual resolution of symptoms. Operative management may be required in the setting of complete nerve injury. Purpose: We present a case detailing our experience managing a patient with a complete median nerve transection following shoulder arthroscopy for a rotator cuff injury. Case Description: A thirty-nine-year-old female was referred to our office five months after undergoing a shoulder arthroscopy for a rotator cuff repair. Upon waking up from her initial surgery, she reported pain, numbness, and weakness in her right arm and hand, including the inability to make a fist or fully flex her first or second fingers. She was found to have right thenar eminence atrophy. Motor exam revealed profound weakness in flexors of the thumb and index finger. Because of the high likelihood of median nerve injury given the patient’s clinical presentation and surgical history along with an unremarkable brachial plexus MRI, surgery was recommended. Upon surgical exposure, the median nerve was found to be completely transected with a large neuroma. The neuroma was removed, and the nerve ends were trimmed with a sural nerve graft used to complete the repair. At her one and a half year follow up, she continued to demonstrate improvement although still complained of numbness in her first three fingers and weakness in her right hand. However, unlike preoperatively, her pain was well-controlled. Conclusion: Although distal neuropathies are a common preoperative complaint of patients with rotator cuff injuries, new onset nerve injuries as a complication from surgical repair should not be overlooked. Prevention of nerve injury is critical through adequate exposure and positioning during surgery. If a nerve injury does occur, examination during follow up visits are critical for monitoring the progression of symptoms and need for additional interventions.

Stress granules (SGs) are non-membrane bound cytoplasmic condensates that form in response to a variety of different stressors. Canonical SGs are thought to have a cytoprotective role, reallocating cellular resources during stress by activation of the integrated stress response (ISR) to inhibit translation and avoid apoptosis. However, different stresses result in compositionally distinct, non-canonical SG formation that is likely pro-apoptotic, though the exact function(s) of both SGs subtypes remain unclear. A unique non-canonical SG subtype is triggered upon exposure to ultraviolet (UV) radiation. While it is generally agreed that UV SGs are bona fide SGs due to their dependence upon the core SG nucleating protein Ras GTPase-activating protein-binding protein 1 (G3BP1), the localization of other key components of UV SGs are unknown or under debate. Further, the dynamics of UV SGs are not known, though unique properties such as cell cycle dependence have been observed. This Perspective compiles the available information on SG subtypes and on UV SGs in particular in an attempt to understand the formation, dynamics, and function of these mysterious stress-specific complexes. We identify key gaps in knowledge related to UV SGs, and examine the unique aspects of their formation. We propose that more thorough knowledge of the distinct properties of UV SGs will lead to new avenues of understanding of the function of SGs, as well as their roles in disease.

Abstract Background Percutaneous mitral valve (MV) clipping for mitral regurgitation (MR) revolutionized MV repair; however, valve anatomies and pathologies vary. Often multiple clips are required, and predicting this pre-procedurally would be useful. We evaluated pre-procedural predictors for multiple clips. Results We retrospectively analyzed 127 severe MR patients treated by mitral clipping between January 2011 and August 2018. Patients were grouped according to the use of a single (group I) or multiple clips (group II) and pre-procedure echocardiographs compared. No demographic differences existed except group II had more males (68.1%) than group I (48.3%). Mean left atrial diameter was larger in group II, 51 ± 9 mm, than group I, 48 ± 5 mm, p = 0.026. Mean mitral annular diameter differed: 34 ± 4mm (group II) versus 33 ± 3 mm (group I), p = 0.017. The vena contracta was broader in group II than group I (6.6 ± 1 mm vs. 6 ± 0.9 mm, p = 0.001). Severe mitral annular calcification occurred more in group I (36.2%) than group II (10.1%), p = 0.0001. On multivariate analysis, vena contracta width correlated positively with multiple clips (B 0.125, p = 0.013), but severe annular calcification correlated inversely (B − 0.35, p = 0.002). Conclusions Vena contracta width and severe annular calcification are factors to consider when planning MV clipping.

Objectives Healthcare personnel have faced unprecedented mental health challenges during the COVID-19 pandemic. The study objective is to assess differences in depression, anxiety, and burnout among healthcare personnel with various occupational roles and whether financial and job strain were associated with these mental health outcomes. Methods We employed an anonymous survey between July and August 2020 at an urban county hospital in California, USA. We assessed depression, anxiety, and burnout using validated scales, and asked questions on financial strain and job strain. We performed logistic and linear regression analyses. Results Nurses (aOR 1.93, 95% CIs 1.12, 3.46), social workers (aOR 2.61, 95% CIs 1.35, 5.17), service workers (aOR 2.55, 95% CIs 1.20, 5.48), and administrative workers (aOR 2.93, 95% CIs 1.57, 5.61) were more likely than physicians to screen positive for depression. The odds of screening positive for anxiety were significantly lower for ancillary workers (aOR 0.32, 95% CIs 0.13–0.72) compared with physicians. Ancillary (aB = -1.77, 95% CIs -1.88, -0.47) and laboratory and pharmacy workers (aB -0.70, 95% CI -1.34, -0.06) reported lower levels of burnout compared with physicians. Financial strain partially accounted for differences in mental health outcomes across job categories. Lack of time to complete tasks and lack of supervisory support were associated with higher odds of screening positive for depression. Less job autonomy was associated with higher odds of screening positive for anxiety and higher burnout levels. Conclusions We found significant disparities in mental health outcomes across occupational roles. Policies to mitigate the adverse impact of COVID-19 on health workers’ mental health should include non-clinical staff and address financial support and job characteristics for all occupational roles.

Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

Summary: Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27–33 weeks of gestation).

A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here, we find that DNA methylation of the TERT CpG island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter mutant cancers. Finally, in several cancers, DNA methylation levels at the TERT CGI correlate with altered patient survival.

We previously published a method that infers chromosome conformation from images of fluorescently-tagged genomic loci, for the case when there are many loci labeled with each distinguishable color. Here we build on our previous work and improve the reconstruction algorithm to address previous limitations. We show that these improvements 1) increase the reconstruction accuracy and 2) allow the method to be used on large-scale problems involving several hundred labeled loci. Simulations indicate that full-chromosome reconstructions at 1/2 Mb resolution are possible using existing labeling and imaging technologies. The updated reconstruction code and the script files used for this paper are available at: https://github.com/heltilda/align3d.

We previously published a method that infers chromosome conformation from images of fluorescently-tagged genomic loci, for the case when there are many loci labeled with each distinguishable color. Here we build on our previous work and improve the reconstruction algorithm to address previous limitations. We show that these improvements 1) increase the reconstruction accuracy and 2) allow the method to be used on large-scale problems involving several hundred labeled loci. Simulations indicate that full-chromosome reconstructions at 1/2 Mb resolution are possible using existing labeling and imaging technologies. The updated reconstruction code and the script files used for this paper are available at: https://github.com/heltilda/align3d.

We previously published a method that infers chromosome conformation from images of fluorescently-tagged genomic loci, for the case when there are many loci labeled with each distinguishable color. Here we build on our previous work and improve the reconstruction algorithm to address previous limitations. We show that these improvements 1) increase the reconstruction accuracy and 2) allow the method to be used on large-scale problems involving several hundred labeled loci. Simulations indicate that full-chromosome reconstructions at 1/2 Mb resolution are possible using existing labeling and imaging technologies. The updated reconstruction code and the script files used for this paper are available at: https://github.com/heltilda/align3d.

MORC3 is linked to inflammatory myopathies and cancer; however, the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA, but it is negatively regulated by the CW domain, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing MORC3 functions and suggest that its modulation may contribute to human disease.

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormone-dependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosterone-dependent malignancy results in the development of prolactin-dependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.