Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Regional Blocks Benefit Patients Undergoing Bilateral Mastectomy with Immediate Implant-Based Reconstruction, Even After Discharge.

BACKGROUND: There is limited evidence that regional anesthesia reduces pain in patients undergoing mastectomy with immediate implant-based reconstruction. We sought to determine whether regional blocks reduce opioid consumption and improve post-discharge patient-reported pain in this population. METHODS: We retrospectively reviewed patients who underwent bilateral mastectomy with immediate implant-based reconstruction with and without a regional block. We tested for differences in opioid consumption by block receipt using multivariable ordinal regression, and also assessed routinely collected patient-reported outcomes (PROs) for 10 days postoperatively and tested the association between block receipt and moderate or greater pain. RESULTS: Of 754 patients, 89% received a block. Non-block patients had an increase in the odds of requiring a higher quartile of postoperative opioids. Among block patients, the estimated probability of being in the lowest quartile of opioids required was 25%, compared with 15% for non-block patients. Odds of patient-reported moderate or greater pain after discharge was 0.54 times lower in block patients than non-block patients (p = 0.025). Block patients had a 49% risk of moderate or greater pain compared with 64% in non-block patients on postoperative day 5. There was no indication of any reason for these differences other than a causal effect of the block. CONCLUSION: Receipt of a regional block resulted in reduced opioid use and lower risk of self-reported moderate and higher pain after discharge in bilateral mastectomy with immediate implant-based reconstruction patients. Our use of PROs suggests that the analgesic effects of blocks persist after discharge, beyond the expected duration of a 'single shot' block.

Nuclear F-actin and myosins drive relocalization of heterochromatic breaks.

Heterochromatin mainly comprises repeated DNA sequences that are prone to ectopic recombination. In Drosophila cells, 'safe' repair of heterochromatic double-strand breaks by homologous recombination relies on the relocalization of repair sites to the nuclear periphery before strand invasion. The mechanisms responsible for this movement were unknown. Here we show that relocalization occurs by directed motion along nuclear actin filaments assembled at repair sites by the Arp2/3 complex. Relocalization requires nuclear myosins associated with the heterochromatin repair complex Smc5/6 and the myosin activator Unc45, which is recruited to repair sites by Smc5/6. ARP2/3, actin nucleation and myosins also relocalize heterochromatic double-strand breaks in mouse cells. Defects in this pathway result in impaired heterochromatin repair and chromosome rearrangements. These findings identify de novo nuclear actin filaments and myosins as effectors of chromatin dynamics for heterochromatin repair and stability in multicellular eukaryotes.

Beyond the cuff: a consideration of factors that affect sexual function after benign hysterectomy.

PURPOSE OF REVIEW: Hysterectomy is the most common gynecologic surgical procedure performed on women in the United States. While there are data supporting that hysterectomy for benign indication often does not reduce sexual function and may in fact improve sexual function as fibroids and endometriosis are resected, it remains unclear if there are factors within the perioperative period that affect sexual function in the years following surgery. To date, there is no consensus on what factors can optimize patients' sexual function after hysterectomy. RECENT FINDINGS: We present the current literature that assesses factors which may contribute to sexual function after hysterectomy. Preoperative demographic factors, including increasing age, pelvic pain, and preoperative sexual dysfunction, play a large role in postoperative sexual function. Perioperatively, there is a growing amount of data suggesting that premenopausal salpingo-oophorectomy at the time of hysterectomy may increase the risk of sexual dysfunction after hysterectomy, and no conclusive evidence that subtotal hysterectomy improves sexual function. The route of hysterectomy and technique of cuff closure can impact sexual function after hysterectomy due to the risk of shortening the vaginal length. SUMMARY: There is a lack of high-quality evidence that can provide a consensus on factors to optimize sexual function after hysterectomy. A growing area of research in the excision of endometriosis procedures is the consideration of nerve-sparing surgery. Considering the many variables that exist when counseling a patient on benign hysterectomy and its effects on sexual function, it is critical to understand the current research that exists with regards to these factors.

Optimizing accrual to a large-scale, clinically integrated randomized trial in anesthesiology: A 2-year analysis of recruitment.

BACKGROUND: Performing large randomized trials in anesthesiology is often challenging and costly. The clinically integrated randomized trial is characterized by simplified logistics embedded into routine clinical practice, enabling ease and efficiency of recruitment, offering an opportunity for clinicians to conduct large, high-quality randomized trials under low cost. Our aims were to (1) demonstrate the feasibility of the clinically integrated trial design in a high-volume anesthesiology practice and (2) assess whether trial quality improvement interventions led to more balanced accrual among study arms and improved trial compliance over time. METHODS: This is an interim analysis of recruitment to a cluster-randomized trial investigating three nerve block approaches for mastectomy with immediate implant-based reconstruction: paravertebral block (arm 1), paravertebral plus interpectoral plane blocks (arm 2), and serratus anterior plane plus interpectoral plane blocks (arm 3). We monitored accrual and consent rates, clinician compliance with the randomized treatment, and availability of outcome data. Assessment after the initial year of implementation showed a slight imbalance in study arms suggesting areas for improvement in trial compliance. Specific improvement interventions included increasing the frequency of communication with the consenting staff and providing direct feedback to clinician investigators about their individual recruitment patterns. We assessed overall accrual rates and tested for differences in accrual, consent, and compliance rates pre- and post-improvement interventions. RESULTS: Overall recruitment was extremely high, accruing close to 90% of the eligible population. In the pre-intervention period, there was evidence of bias in the proportion of patients being accrued and receiving the monthly block, with higher rates in arm 3 (90%) compared to arms 1 (81%) and 2 (79%, p = 0.021). In contrast, in the post-intervention period, there was no statistically significant difference between groups (p = 0.8). Eligible for randomization rate increased from 89% in the pre-intervention period to 95% in the post-intervention period (difference 5.7%; 95% confidence interval = 2.2%-9.4%, p = 0.002). Consent rate increased from 95% to 98% (difference of 3.7%; 95% confidence interval = 1.1%-6.3%; p = 0.004). Compliance with the randomized nerve block approach was maintained at close to 100% and availability of primary outcome data was 100%. CONCLUSION: The clinically integrated randomized trial design enables rapid trial accrual with a high participant compliance rate in a high-volume anesthesiology practice. Continuous monitoring of accrual, consent, and compliance rates is necessary to maintain and improve trial conduct and reduce potential biases. This trial methodology serves as a template for the implementation of other large, low-cost randomized trials in anesthesiology.

Plasmonic Response of Complex Nanoparticle Assemblies.

Optical properties of nanoparticle assemblies reflect distinctive characteristics of their building blocks and spatial organization, giving rise to emergent phenomena. Integrated experimental and computational studies have established design principles connecting the structure to properties for assembled clusters and superlattices. However, conventional electromagnetic simulations are too computationally expensive to treat more complex assemblies. Here we establish a fast, materials agnostic method to simulate the optical response of large nanoparticle assemblies incorporating both structural and compositional complexity. This many-bodied, mutual polarization method resolves limitations of established approaches, achieving rapid, accurate convergence for configurations including thousands of nanoparticles, with some overlapping. We demonstrate these capabilities by reproducing experimental trends and uncovering far- and near-field mechanisms governing the optical response of plasmonic semiconductor nanocrystal assemblies including structurally complex gel networks and compositionally complex mixed binary superlattices. This broadly applicable framework will facilitate the design of complex, hierarchically structured, and dynamic assemblies for desired optical characteristics.

Growing pains: strategies for improving ergonomics in minimally invasive gynecologic surgery.

PURPOSE OF REVIEW: To evaluate factors contributing to the development of work-related musculoskeletal disorders (WMSDs) and review strategies for mitigating ergonomic strain in minimally invasive gynecologic surgery. RECENT FINDINGS: Factors associated with increased ergonomic strain and the development of WMSDs include increasing patient body mass index (BMI), smaller surgeon hand size, noninclusive design of instruments and energy devices and improper positioning of surgical equipment. Each type of minimally invasive surgery (laparoscopic, robotic, vaginal) confers its own ergonomic risk to the surgeon. Recommendations have been published regarding optimal ergonomic surgeon and equipment positioning. Intraoperative breaks and stretching are effective in reducing surgeon discomfort. Formal training in ergonomics has not yet been widely implemented, but educational interventions have been effective in reducing surgeon discomfort and can improve surgeon recognition of suboptimal ergonomics. SUMMARY: Considering the serious downstream effects of WMSDs on surgeons, it is imperative to implement strategies for WMSD prevention. Optimal positioning of the surgeons and operative equipment should be routine. Intraoperative breaks and stretching should be incorporated during procedures and between every case. Formal education in ergonomics should be provided to surgeons and trainees. Additionally, more inclusive instrument design by industry partners should be prioritized.

Combined coronary artery bypass graft and liver/kidney transplantation in a liver failure patient with acute on chronic kidney failure and antiphospholipid syndrome.

Coexisting coronary artery disease (CAD), end-stage liver disease (ESLD), renal failure, and hypercoagulable state poses a formidable clinical challenge. Here, we discuss the first known case of a patient with antiphospholipid syndrome (APLS), ESLD complicated by hepatorenal syndrome (HRS), and severe CAD who successfully underwent combined coronary artery bypass grafting (CABG) and simultaneous liver/kidney (SLK) transplant.

The Cost of Guideline Adherence: A Multicenter Analysis of the Financial Implications of Adopting the US Multi-Society Task Force Polypectomy Guidelines.

GOAL: The goal of this study was to determine the financial impact of adopting the US Multi-Society Task Force (USMSTF) polypectomy guidelines on physician reimbursement and disposable equipment costs for gastroenterologists in the academic medical center and community practice settings. BACKGROUND: In 2020, USMSTF guidelines on polypectomy were introduced with a strong recommendation for cold snare rather than cold forceps technique for removing diminutive and small polyps. Polypectomy with snare technique reimburses physicians at a higher rate compared with cold forceps and also requires different disposable equipment. The financial implications of adopting these guidelines is unknown. MATERIALS AND METHODS: Patients that underwent screening colonoscopy where polypectomy was performed at an academic medical center (Loma Linda University Medical Center) and community practice medical center (Ascension Providence Hospital) between July 2018 and July 2019 were identified. The polypectomy technique performed during each procedure was determined (forceps alone, snare alone, forceps plus snare) along with the number and size of polyps as well as disposable equipment. Actual and projected provider reimbursement and disposable equipment costs were determined based on applying the new polypectomy guidelines. RESULTS: A total of 1167 patients underwent colonoscopy with polypectomy. Adhering to new guidelines would increase estimated physician reimbursement by 5.6% and 12.5% at academic and community practice sites, respectively. The mean increase in physician reimbursement per procedure was significantly higher at community practice compared with the academic setting ($29.50 vs. $14.13, P <0.00001). The mean increase in disposable equipment cost per procedure was significantly higher at the community practice setting ($6.11 vs. $1.97, P <0.00001). CONCLUSION: Adopting new polypectomy guidelines will increase physician reimbursement and equipment costs when colonoscopy with polypectomy is performed.

Cumulative summation analysis of learning curve for robotic-assisted hiatal hernia repairs.

BACKGROUND: Robotic-assisted laparoscopic surgery (RALS) is evolving as an important surgical approach in the field of general surgery. We aimed to evaluate the learning curve for RALS procedures involving repair of hiatal hernias. METHODS: A series of robotic-assisted hiatal hernia (HH) repairs were performed between 2013 and 2017 by a surgeon at a single institution. Data were entered into a retrospective database. Patient demographics and intraoperative parameters including console time (CT), surgery time (ST), and total operative time (OT) were examined and abstracted for learning curve analysis using the cumulative sum (CUSUM) method. Assessment of perioperative and post-operative outcomes were calculated using descriptive statistics. RESULTS: The average age of the patients was 57.4 years, average BMI was 29.9 kg/m2, median American Society of Anesthesiologists (ASA) classification was 2, and average Charlson Comorbidity Index (CCI) score was 2.8. The series had a mean CT of 132.6 min, mean ST of 145.1 min, and mean OT of 197.4 min. The CUSUM learning curve for CT was best approximated as a third-order polynomial consisting of three unique phases: the initial training phase (case 1-40), the improvement phase (case 41-85), and the mastery phase (case 86 onwards). There was no significant difference in perioperative complications between the phases. Short-term clinical outcomes were comparable with national standards and did not correlate significantly with operative experience. CONCLUSIONS: The three phases identified with CUSUM analysis represented characteristic stages of the learning curve for robotic hiatal hernia procedures. Our data suggest the training phase is achieved after 40 cases and a high level of mastery is achieved after approximately 85 cases. Thus, the CUSUM method serves as a useful tool for objectively evaluating practical skills for surgeons and can ultimately help establish milestones that assess surgical competency during robotic surgery training.

The landscape of chimeric RNAs in non-diseased tissues and cells.

Chimeric RNAs and their encoded proteins have been traditionally viewed as unique features of neoplasia, and have been used as biomarkers and therapeutic targets for multiple cancers. Recent studies have demonstrated that chimeric RNAs also exist in non-cancerous cells and tissues, although large-scale, genome-wide studies of chimeric RNAs in non-diseased tissues have been scarce. Here, we explored the landscape of chimeric RNAs in 9495 non-diseased human tissue samples of 53 different tissues from the GTEx project. Further, we established means for classifying chimeric RNAs, and observed enrichment for particular classifications as more stringent filters are applied. We experimentally validated a subset of chimeric RNAs from each classification and demonstrated functional relevance of two chimeric RNAs in non-cancerous cells. Importantly, our list of chimeric RNAs in non-diseased tissues overlaps with some entries in several cancer fusion databases, raising concerns for some annotations. The data from this study provides a large repository of chimeric RNAs present in non-diseased tissues, which can be used as a control dataset to facilitate the identification of true cancer-specific chimeras.

Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease.

Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.

Effect of surface properties and polymer chain length on polymer adsorption in solution.

In polymer nanoparticle composites (PNCs) with attractive interactions between nanoparticles (NPs) and polymers, a bound layer of the polymer forms on the NP surface, with significant effects on the macroscopic properties of the PNCs. The adsorption and wetting behaviors of polymer solutions in the presence of a solid surface are critical to the fabrication process of PNCs. In this study, we use both classical density functional theory (cDFT) and molecular dynamics (MD) simulations to study dilute and semi-dilute solutions of short polymer chains near a solid surface. Using cDFT, we calculate the equilibrium properties of polymer solutions near a flat surface while varying the solvent quality, surface-fluid interactions, and the polymer chain lengths to investigate their effects on the polymer adsorption and wetting transitions. Using MD simulations, we simulate polymer solutions near solid surfaces with three different curvatures (a flat surface and NPs with two radii) to study the static conformation of the polymer bound layer near the surface and the dynamic chain adsorption process. We find that the bulk polymer concentration at which the wetting transition in the poor solvent system occurs is not affected by the difference in surface-fluid interactions; however, a threshold value of surface-fluid interaction is needed to observe the wetting transition. We also find that with good solvent, increasing the chain length or the difference in the surface-polymer interaction relative to the surface-solvent interaction increases the surface coverage of polymer segments and independent chains for all surface curvatures. Finally, we demonstrate that the polymer segmental adsorption times are heavily influenced only by the surface-fluid interactions, although polymers desorb more quickly from highly curved surfaces.

Investigating the effects of a virtual reality-based stress management programme on inpatients with mental disorders: A pilot randomised controlled trial.

This study aimed to examine the effects and feasibility of a virtual screen-based stress management programme (V-DESSERTS) on inpatients with mental disorders. A single-blinded, pilot randomised controlled trial was conducted in a tertiary hospital in Singapore. Convenience sampling was used and participants were randomised into either the intervention group or the waitlisted control group (WL). The intervention group received individual-based, twice-daily sessions of the programme. Each session comprised education and virtual screen-based relaxation practice. Data were collected through self-reported questionnaires and physiological measures. The intervention group showed a significant increase in perceived relaxation and knowledge in comparison with the WL group. However, inconclusive results were observed on subjective and objective stress. The findings in this study indicated that the V-DESSERTS programme is feasible to be implemented for patients with schizophrenia, depression and bipolar disorders.

Effect of polymer-nanoparticle interaction on strain localization in polymer nanopillars.

Polymer nanocomposites (PNCs), a class of composites consisting of typically inorganic nanoparticles (NPs) embedded in a polymer matrix, have become an emerging class of materials due to their significant potential to combine the functionality of NPs with the toughness of polymers. However, many applications are limited by their mechanical properties, and a fundamental understanding of NPs' effect on the nonlinear mechanical properties is lacking. In this study, we used molecular dynamics simulations to investigate the influence of NPs on the tendency of a polymer nanopillar to form a shear band. Even though we restrict ourselves to sufficiently low NP loadings that the elastic and yield behaviors are unaffected compared to the pure polymer, the polymer-NP interactions have a surprisingly strong effect on the location of a shear band in the sample. Different polymer-NP interactions have been used to explore their effect on the local structure of materials which is described using a recently developed machine-learned quantity, softness. Our calculations reveal a strong correlation between the strain localization pattern and the local structural signatures. Lastly, we show that weak interactions between NP and polymer matrix can form a soft region near the NP, and this leads to an attraction of the shear band to the NP surface.

Functional heritage: the evolution of chimeric RNA into a gene.

Once believed to be unique features of neoplasia, chimeric RNAs are now being discovered in normal physiology. We speculated that some chimeric RNAs may be functional precursors of genes, and that forming chimeric RNA at the transcriptional level may be a 'trial' mechanism before the functional element is fixed into the genome. Supporting this idea, we identified a chimeric RNA, HNRNPA1L2-SUGT1 (H-S), whose sequence is highly similar to that of a 'pseudogene' MRPS31P5. Sequence analysis revealed that MRPS31P5 transcript is more similar to H-S chimeric RNA than its 'parent' gene, MRPS31. Evolutionarily, H-S precedes MRPS31P5, as it can be detected bioinformatically and experimentally in marmosets, which do not yet possess MRPS31P5 in their genome. Conversely, H-S is minimally expressed in humans, while instead, MRPS31P5 is abundantly expressed. Silencing H-S in marmoset cells resulted in similar phenotype as silencing MRPS31P5 in human cells. In addition, whole transcriptome analysis and candidate downstream target validation revealed common signalling pathways shared by the two transcripts. Interestingly, H-S failed to rescue the phenotype caused by silencing MPRS31P5 in human and rhesus cells, whereas MRPS31P5 can at least partially rescue the phenotype caused by silencing H-S in marmoset cells, suggesting that MRPS31P5 may have further evolved into a distinct entity. Thus, multiple lines of evidence support that MRPS31P5 is not truly a pseudogene of MRPS31, but a likely functional descendent of H-S chimera. Instead being a gene fusion product, H-S is a product of cis-splicing between adjacent genes, while MRPS31P5 is likely produced by genome rearrangement.

Leptomeningeal Metastases in Non-small Cell Lung Cancer: Optimal Systemic Management in NSCLC With and Without Driver Mutations.

OPINION STATEMENT: As a devastating complication of non-small cell lung cancer (NSCLC), the incidence of leptomeningeal metastasis (LM) is rising, largely due to overall longer survival of NSCLC, especially in patients with targetable molecular driver mutations. There is no clear consensus on the optimal management of LM. This review will cover recent advances in diagnosis, monitoring, and treatment of LM in NSCLC. In LM without oncogene drivers, systemic chemotherapy, intrathecal therapy, and radiation have modestly improved the clinical outcomes. Emerging data have also suggested encouraging activity of immunotherapy. At the same time, in LM with sensitizing EGFR mutations, osimertinib should be considered regardless of T790M status. Pulse erlotinib, afatinib, and newer agents with improved CNS penetration have also shown benefits. Moreover, accumulating evidences support potential benefits of molecularly targeted therapy in ALK-rearranged and other oncogene-driven NSCLC with LM. Future studies are warranted to better define the underlying mechanism, to optimize the clinical management, and to improve patient outcomes.

The Impact of Comprehensive Community Initiatives on Population-Level Child, Youth, and Family Outcomes: A Systematic Review.

Comprehensive community initiatives (CCIs) represent a popular method for creating systemic change, yet there is a dearth of evidence on their effectiveness (Zaff, Pufall Jones, Donlan, Lin, & Anderson, 2016). This article presents a systematic review of the evidence on the population-level impact of CCIs, focusing specifically on documented effects from studies using an experimental or quasi-experimental design. Of 1,947 articles identified through a database and hand search, 25 articles examining six different CCIs-most of which employed prevention science frameworks-met the review inclusion criteria. The results of this review show that CCIs can strengthen protective factors and reduce risk factors, delay initiation of and reduce substance use, and reduce the likelihood of, and delay engagement in, violent and/or delinquent behaviors. Impacts have been documented as soon as one year after initial intervention, and as early as 7th grade, with effects sustained as long as seven years post-intervention, and as late as a year post-high school. However, relative to the prevalence of CCIs as a practical intervention, the evidence base is small, potentially dated, and focused on a narrow set of outcomes and populations. Recommendations for interpreting the evidence base are discussed, including methodological limitations and implications for future work.

Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.