Inflammatory macrophage to hepatocyte signals can be prevented by extracellular vesicle reprogramming.

Macrophage-derived extracellular vesicles (EVs) play key roles in intercellular communication. Within the liver, they have been linked to several inflammatory diseases including nonalcoholic fatty liver disease (NAFLD). In this study, we found that inflammatory macrophages cause injury to hepatocytes, in part by a cell-cell crosstalk phenomenon involving the secretion of EVs containing pro-inflammatory cargo. Incorporation of these inflammatory signals into EV requires the cleavage of the trafficking adaptor protein RILP, which, as previously shown, results from inflammasome-mediated caspase-1 activation. RILP cleavage can be blocked by overexpressing a dominant negative, non-cleavable form of RILP (ncRILP). EV preparations from ncRILP-expressing cells are, by themselves, sufficient to suppress inflammatory effects in hepatocytes. These results suggest that both direct RILP manipulation and/or supplying ncRILP-modified EVs could be used as a novel therapy for the treatment of inflammatory liver diseases.

Kupffer cell diversity maintains liver function in alcohol-associated liver disease.

BACKGROUND AND AIMS: Liver macrophages are heterogeneous and play an important role in alcohol-associated liver disease (ALD) but there is limited understanding of the functions of specific macrophage subsets in the disease. We used a Western diet alcohol (WDA) mouse model of ALD to examine the hepatic myeloid cell compartment by single cell RNAseq and targeted KC ablation to understand the diversity and function of liver macrophages in ALD. APPROACH AND RESULTS: In the WDA liver, KCs and infiltrating monocytes/macrophages each represented about 50% of the myeloid pool. Five major KC clusters all expressed genes associated with receptor-mediated endocytosis and lipid metabolism, but most were predicted to be noninflammatory and antifibrotic with 1 minor KC cluster having a proinflammatory and extracellular matrix degradation gene signature. Infiltrating monocyte/macrophage clusters, in contrast, were predicted to be proinflammatory and profibrotic. In vivo, diphtheria toxin-based selective KC ablation during alcohol exposure resulted in a liver failure phenotype with increases in PT/INR and bilirubin, loss of differentiated hepatocyte gene expression, and an increase in expression of hepatocyte progenitor markers such as EpCAM, CK7, and Igf2bp3. Gene set enrichment analysis of whole-liver RNAseq from the KC-ablated WDA mice showed a similar pattern as seen in human alcoholic hepatitis. CONCLUSIONS: In this ALD model, KCs are anti-inflammatory and are critical for the maintenance of hepatocyte differentiation. Infiltrating monocytes/macrophages are largely proinflammatory and contribute more to liver fibrosis. Future targeting of specific macrophage subsets may provide new approaches to the treatment of liver failure and fibrosis in ALD.

Polyethylene bearing wear is comparable for cemented and cementless Oxford unicompartmental knee replacements: Ten-year results of a randomized controlled trial.

PURPOSE: There is concern that using cementless components may increase polyethylene wear of the Oxford unicompartmental knee replacement (OUKR). Therefore, this study aimed to measure bearing wear at 10 years in patients from a randomized trial comparing Phase 3 cemented and cementless OUKRs and to investigate factors that may affect wear. It was hypothesized that there would be no difference in wear rate between cemented and cementless OUKRs. METHODS: Bearing thickness was determined using radiostereometric analysis at postoperative, 3-month, 6-month, 1-year, 2-year, 5-year and 10-year timepoints. As creep occurs early, wear rate was calculated using linear regression between 6 months and 10 years for 39 knees (20 cemented, 19 cementless). Associations between wear and implant, surgical and patient factors were analysed. RESULTS: The linear wear rate of the Phase 3 OUKR was 0.06 mm/year with no significant difference (p = 0.18) between cemented (0.054 mm/year) and cementless (0.063 mm/year) implants. Age, Oxford Knee Score, component size and bearing thickness had no correlation with wear. A body mass index ≥ 30 was associated with a significantly lower wear rate (p = 0.007) as was having ≥80% femoral component contact area on the bearing (p = 0.003). Bearings positioned ≥1.5 mm from the tibial wall had a significantly higher wear rate (p = 0.002). CONCLUSIONS: At 10 years, the Phase 3 OUKR linear wear rate is low and not associated with the fixation method. To minimize the risk of wear-related bearing fracture in the very long-term surgeons should consider using 4 mm bearings in very young active patients and ensure that components are appropriately positioned, which is facilitated by the current instrumentation. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Efficacy of Individualized Homeopathic Medicines in Pre-diabetes.

BACKGROUND: Pre-diabetes (PD) contributes importantly to the disease burden worldwide and is a precursor to stroke, cardiovascular diseases, as well as type-2 diabetes mellitus. OBJECTIVE: In this project, the efficacy of individualized homeopathic medicines (IHMs) was explored against placebos in the treatment of PD. METHODS: A 6-month, double-blind, randomized, placebo-controlled trial was conducted at the outpatient departments of a homeopathic medical college and hospital in India. Sixty participants with PD were randomized to receive either IHMs (n = 30) or identical-looking placebos (n = 30). Concomitant care measures were advised to both groups of participants in terms of dietary advice, yoga, meditation and exercise. The primary outcome measures were fasting blood sugar (FBS) and the oral glucose tolerance test (OGTT); the secondary outcome was the Diabetes Symptom Checklist-Revised (DSC-R) score. All the outcomes were measured at baseline and after 3 and 6 months of treatment. Inter-group differences and effect sizes (Cohen's d) were calculated using two-way repeated measures analysis of variance models after adjusting baseline differences using analysis of co-variance on the intention-to-treat data. RESULTS: Between-group differences for FBS were statistically significant, favoring IHMs against placebos (F 1,58 = 7.798, p = 0.007), but not for OGTT (F 1,58 = 1.691, p = 0.199). The secondary outcome, DSC-R total score, favoring IHMs significantly compared with placebos (F 1,58 = 15.752, p < 0.001). Calcarea Carbonicum, Thuja occidentalis and Sulphur were the most frequently prescribed medicines. No harm or serious adverse events were recorded from either of the participant groups. CONCLUSION: IHMs produced significantly better results than placebos in FBS and in DSC-R scores but not in OGTT. Independent replications with larger sample sizes are warranted to substantiate the findings. TRIAL REGISTRATION: CTRI/2019/10/021711.

Predicting Human Dermal Drug Concentrations Using PBPK Modeling and Simulation: Clobetasol Propionate Case Study.

Quantitative in silico tools may be leveraged to mechanistically predict the dermato-pharmacokinetics of compounds delivered from topical and transdermal formulations by integrating systems of rate equations that describe permeation through the formulation and layers of skin and pilo-sebaceous unit, and exchange with systemic circulation via local blood flow. Delivery of clobetasol-17 propionate (CP) from DermovateTM cream was simulated using the Transdermal Compartmental Absorption & Transit (TCATTM) Model in GastroPlus®. The cream was treated as an oil-in-water emulsion, with model input parameters estimated from publicly available information and quantitative structure-permeation relationships. From the ranges of values available for model input parameters, a set of parameters was selected by comparing model outputs to CP dermis concentration-time profiles measured by dermal open-flow microperfusion (Bodenlenz et al. Pharm Res. 33(9):2229-38, 2016). Predictions of unbound dermis CP concentrations were reasonably accurate with respect to time and skin depth. Parameter sensitivity analyses revealed considerable dependence of dermis CP concentration profiles on drug solubility in the emulsion, relatively less dependence on dispersed phase volume fraction and CP effective diffusivity in the continuous phase of the emulsion, and negligible dependence on dispersed phase droplet size. Effects of evaporative water loss from the cream and corticosteroid-induced vasoconstriction were also assessed. This work illustrates the applicability of computational modeling to predict sensitivity of dermato-pharmacokinetics to changes in thermodynamic and transport properties of a compound in a topical formulation, particularly in relation to rate-limiting steps in skin permeation. Where these properties can be related to formulation composition and processing, such a computational approach may support the design of topically applied formulations.

Neuromodulation for the management of chronic pelvic pain syndromes: A systematic review.

BACKGROUND: Chronic pelvic pain is a burdensome condition that involves multiple medical sub-specialties and is often difficult to treat. Sacral stimulation for functional bladder disease has been well established, but little large-scale evidence exists regarding utilization of other neuromodulation techniques to treat chronic pelvic pain. Emerging evidence does suggest that neuromodulation is a promising treatment, and we aim to characterize the use and efficacy of such techniques for treating chronic pelvic pain syndromes. MATERIALS AND METHODS: A systematic review of the literature demonstrating the treatment of chronic pelvic pain syndromes with neuromodulation. Abstracts were reviewed and selected for inclusion, including case series, prospective studies, and randomized controlled trials (RCTs). Case studies and publications in abstract only were not included. The reporting for this systematic review follows Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The literature search was performed using MEDLINE, Embase, Cochrane Library, PubMed, CINAHL, and Scopus. RESULTS: A total of 50 studies were included in this review, three of which were randomized controlled trials, and the remaining were prospective and retrospective case series. The range of pelvic pain conditions treated included interstitial cystitis, peripheral neuralgia, pudendal neuralgia, gastrointestinal pain, urogenital pain, sacroiliac joint pain, and visceral chronic pelvic pain. We reported on outcomes involving pain, functionality, psychosocial improvement, and medication reduction. CONCLUSIONS: Neuromodulation is a growing treatment for various chronic pain syndromes. Peripheral nerve stimulation was the least studied form of stimulation. Posterior tibial nerve stimulation appears to offer short-term benefit, but long-term results are challenging. Sacral nerve stimulation is established for use in functional bladder syndromes and appears to offer pain improvement in these patients as well. Dorsal root ganglion stimulation and spinal cord stimulation have been used for a variety of conditions with promising results. Further studies of homogeneous patient populations are necessary before strong recommendations can be made at this time, although pooled analysis may also be impactful.

Parametric separation of phase-locked and non-phase-locked activity.

Brain dynamics recorded via electroencephalography (EEG) is conceptualized as a sum of two components: "phase-locked" and "non-phase-locked" to the stimulus. Phase-locked activity is often implicitly studied as event-related potentials (ERPs), and the trial-averaged estimates-evoked potentials (EP) considered both time-locked and phase-locked to the stimulus. The non-phase-locked activity, on the other hand, refers to an increase in power in a narrow band or broadband frequencies in the signal emerging at variable phases from stimulus initiation. Both components are understood to stem from different neuronal mechanisms; hence, accurately characterizing them is of immense importance to neuroscientific studies. Here, we discuss the drawbacks of currently used methods to separate the phase-locked and non-phase-locked activity and propose a novel concurrent phaser method (CPM) that simultaneously decomposes the two components. First, we establish that the single-trial separation of phase-locked and non-phase-locked power is an ill-posed problem. Second, using simulations where ground truth validation is possible, we elucidate how the estimation of non-phase-locked power gets biased by phase-locked power in the state-of-the-art averaging method and ways to resolve the issue using CPM. Next, we use two experimental EEG datasets-audio oddball and auditory steady-state responses (ASSR) to show that empirical signal-to-noise estimates warrant the usage of CPM to separate phase-locked and non-phase-locked activity. Thus, using ground truth validation from simulations and demonstration in real experimental scenarios, the efficacy of the proposed CPM is established.NEW & NOTEWORTHY Parametric models for estimation of phase-locked and non-phase-locked brain signals reveals how estimation of non-phase-locked component is biased by the variability of phase-locked component and at the level of single trial becomes an ill-posed problem. Furthermore, the modeling framework delimits the boundaries where traditional averaging approach can be trusted to estimate the phase-locked and non-phase-locked components.

Individualized Homeopathic Medicines in Treatment of Hyperuricemia: Evaluation by Double-Blind, Randomized, Placebo-Controlled Trial.

INTRODUCTION: Hyperuricemia (HU) is a major health issue in India and across the globe. It increases the disease burden and hampers quality of life. This study was aimed at exploring the effects of individualized homeopathic medicines (IHMs) against placebo in the treatment of HU. METHODS: This double-blind, randomized, placebo-controlled trial was conducted on 60 patients suffering from HU in the outpatient department of D. N. De Homoeopathic Medical College and Hospital, Kolkata. Each patient received either IHMs or identical-looking placebos, along with advice on dietary modifications irrespective of codes. Serum uric acid (SUA) level was the primary outcome measure; the HU quality of life questionnaire (HUQLQ) and the Measure Yourself Medical Outcome Profile version 2 (MYMOP-2) were the secondary outcomes; all measured at baseline, and every month, up to 3 months. Group differences were examined by two-way (split-half) repeated-measures analysis of variance after adjusting for baseline differences. Significance level was set at p ≤0.05, two-tailed. RESULTS: The intention-to-treat sample (n = 58) was analyzed. Between-group differences in SUA levels (F 1, 56 = 13.833, p <0.001), HUQLQ scores (F 1, 56 = 32.982, p <0.001) and MYMOP-2 profile scores (F 1, 56 = 23.873, p <0.001) were statistically significant, favoring IHMs against placebos, with medium to large effect sizes. Calcarea carbonica and Pulsatilla nigricans were the most frequently prescribed medicines. No serious adverse events were reported from either of the groups. CONCLUSION: IHMs showed significantly better results than placebos in reducing SUA levels and improving quality of life in patients suffering from HU. TRIAL REGISTRATION: CTRI/2019/10/021503; UTN: U1111-1241-1431.

Individualized Homeopathic Medicines in the Treatment of Knee Osteoarthritis: Double-Blind, Randomized, Placebo-Controlled Feasibility Trial.

INTRODUCTION: This study aimed at examining the feasibility issues of comparing individualized homeopathic medicines (IHMs) with identical-looking placebos for treating knee osteoarthritis (OA). METHODS: Forty eligible patients participated in this double-blind, randomized (1:1), placebo-controlled feasibility trial in the outpatient clinics of a homeopathic hospital in West Bengal, India. Either IHMs or identical-looking placebos were administered, along with mutually agreed-upon concomitant care guidelines. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was the primary outcome measure, and derived Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores from KOOS, EQ-5D-5L questionnaire, and Visual Analog Scale (VAS) were the secondary outcomes; all measured at baseline and after 2 months. Group differences and effect sizes (Cohen's d) were estimated using an intention-to-treat approach. p-Values less than 0.05 (two-tailed) were considered statistically significant. RESULTS: Enrolment/screening and trial retention rates were 43% and 85% respectively. Recruitment was difficult owing to the coronavirus disease 2019 (COVID-19) lockdown. Group differences were statistically significant, favoring IHMs against placebos in all the KOOS sub-scales: symptoms (p < 0.001), pain (p = 0.002), activities of daily living (p < 0.001), sports or recreation (p = 0.016), and quality of life (p = 0.002). Derived WOMAC scores from KOOS favored IHMs against placebos: stiffness (p < 0.001) and pain (p < 0.001). The EQ-5D-5L questionnaire score (p < 0.001) and EQ-5D-5L VAS scores (p < 0.001) also yielded significant results, favoring IHMs over placebos. All the effect sizes ranged from moderate to large. Sulphur was the most frequently prescribed homeopathic medication. Neither group reported any harm or serious adverse events. CONCLUSION: Although recruitment was sub-optimal due to prevailing COVID-19 conditions during the trial, the action of IHMs was found to be superior to that of placebos in the treatment of knee OA. Larger and more definitive studies, with independent replications, are required to substantiate the findings. TRIAL REGISTRATION: CTRI/2021/02/031453.

Bioequivalence Evaluation of Topical Metronidazole Products Using Dermal Microdialysis in New Zealand Rabbits.

Comparative assessment of cutaneous pharmacokinetics (cPK) by dermal microdialysis (dMD) appears to be suitable to evaluate the bioequivalence (BE) of topical dermatological drug products applied to the skin (TDDPs). Although dMD studies in the literature have reported inconclusive BE assessments, we have addressed several methodological deficiencies to improve dMD's capability to assess BE between reference (R) and approved generic (referred to as test (T)) gel and cream products of metronidazole (MTZ). The 90% confidence interval (CI) of the geometric mean ratios for the Ln(AUC0-24) and Ln(Cmax) endpoints was centered within the BE limits of 80-125%. The CIs extended outside this range as the proof-of-principle study was not statistically powered to demonstrate BE (N = 7 rabbits). A power analysis suggests that, with the variability observed in this study, 21 rabbits for the cream and 11 rabbits for the gel would be sufficient to support an evaluation of BE with the 2 probe replicates we used, and only 10 and 5 rabbits would be sufficient to power the study for the cream and gel, respectively, if 4 probe replicates are used for each treatment per rabbit. These results indicate that dMD when properly controlling variables can be used to support BE assessments for TDDPs.

Importance of NFκß, IL-10 serum levels and DC-SIGN polymorphic haplotypes in determining dengue disease severity among eastern Indian patients.

OBJECTIVES: Dengue viral (DENV) infection is most prevalent arboviral infection in India resulting in wide-range of symptomatic manifestation from simple (DF) to severe dengue (SD). DENV is internalized by dendritic cell receptor, DC-SIGN, which in turn activates inflammatory cytokines: NFκß, IL-10 as adaptive immune response. Present study focused on role of DC-SIGN polymorphisms and these cytokines in SD development among eastern Indian patients. METHOD: DC-SIGN polymorphisms (rs735239, rs4804803, rs2287886) and NFκß, IL-10 concentrations were analysed among 179 dengue patients and 123 healthy individuals by PCR-RFLP and sandwich ELISA, respectively. DENV copies/ml and serotype in patient-sera were measured by quantitative and qualitative real time PCR, respectively. Statistical and haplotype analysis were performed by GraphPad-Prism and SNPStat, respectively. RESULT: Prevalence of DENV serotypes among infected patients: DENV2>DENV4>DENV3>DENV1; those with DENV3 infection reported significantly increased IL-10 level. NFκß and IL-10 concentrations were significantly elevated among SD patients. ROC curve analysis predicted cut-off values of NFκß>13.46 ng/ml and IL-10 > 490.5 pg/ml to detect SD among infected patients with a good sensitivity and specificity. Patients with rs735239-GG, rs2287886-GG genotypes and GGG, GAG haplotypes were significantly associated with SD development, whereas, those with rs4804803-AG exhibited high DENVcopies/ml. Patients with these haplotypes also demonstrated increased NFκß and IL-10. CONCLUSION: This study emphasised importance of DC-SIGN GGG and GAG haplotypes, NFκß and IL-10 concentrations in WHO-defined severe dengue development among infected patients.

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model.

Physiologically based pharmacokinetic (PBPK) modeling has increasingly been employed in dermal drug development and regulatory assessment, providing a framework to integrate relevant information including drug and drug product attributes, skin physiology parameters, and population variability. The current study aimed to develop a stepwise modeling workflow with knowledge gained from modeling in vitro skin permeation testing (IVPT) to describe in vivo exposure of metronidazole locally in the stratum corneum following topical application of complex semisolid drug products. The initial PBPK model of metronidazole in vitro skin permeation was developed using infinite and finite dose aqueous metronidazole solution. Parameters such as stratum corneum lipid-water partition coefficient (Ksclip/water) and stratum corneum lipid diffusion coefficient (Dsclip) of metronidazole were optimized using IVPT data from simple aqueous solutions (infinite) and MetroGel (10 mg/cm2 dose application), respectively. The optimized model, when parameterized with physical and structural characteristics of the drug products, was able to accurately predict the mean cumulative amount permeated (cm2/h) and flux (µg/cm2/h) profiles of metronidazole following application of different doses of MetroGel and MetroCream. Thus, the model was able to capture the impact of differences in drug product microstructure and metamorphosis of the dosage form on in vitro metronidazole permeation. The PBPK model informed by IVPT study data was able to predict the metronidazole amount in the stratum corneum as reported in clinical studies. In summary, the proposed model provides an enhanced understanding of the potential impact of drug product attributes in influencing in vitro skin permeation of metronidazole. Key kinetic parameters derived from modeling the metronidazole IVPT data improved the predictions of the developed PBPK model of in vivo local metronidazole concentrations in the stratum corneum. Overall, this work improves our confidence in the proposed workflow that accounts for drug product attributes and utilizes IVPT data toward improving predictions from advanced modeling and simulation tools.

Trends in outpatient shoulder arthroplasty during the COVID-19 (coronavirus disease 2019) era: increased proportion of outpatient cases with decrease in 90-day readmissions.

BACKGROUND: The COVID-19 (coronavirus disease 2019) pandemic has placed an increased burden on health care resources, with hospitals around the globe canceling or reducing most elective surgical cases during the initial period of the pandemic. Simultaneously, there has been an increased interest in performing outpatient total joint arthroplasty in an efficient manner while maintaining patient safety. The purpose of this study was to investigate trends in total shoulder arthroplasty (TSA) during the COVID-19 era with respect to outpatient surgery and postoperative complications. METHODS: We conducted a retrospective chart review of all primary anatomic and reverse TSAs performed at our health institution over a 3-year period (January 2018 to January 2021). All cases performed prior to March 2020 were considered the "pre-COVID-19 era" cohort. All cases performed in March 2020 or later comprised the "COVID-19 era" cohort. Patient demographic characteristics and medical comorbidities were also collected to appropriately match patients from the 2 cohorts. Outcomes measured included type of patient encounter (outpatient vs. inpatient), total length of stay, and 90-day complications. RESULTS: A total of 567 TSAs met the inclusion criteria, consisting of 270 shoulder arthroplasty cases performed during the COVID-19 era and 297 cases performed during the pre-COVID-19 era. There were no significant differences in body mass index, American Society of Anesthesiologists score, smoking status, or distribution of pertinent medical comorbidities between the 2 examined cohorts. During the COVID-19 era, 31.8% of shoulder arthroplasties were performed in an outpatient setting. This was significantly higher than the percentage in the pre-COVID-19 era, with only 4.5% of cases performed in an outpatient setting (P < .0001). The average length of stay was significantly reduced in the COVID-19 era cohort (0.81 days vs. 1.45 days, P < .0001). There was a significant decrease in 90-day readmissions during the COVID-19 era. No significant difference in 90-day emergency department visits, 90-day venous thromboembolism events, or 90-day postoperative infections was observed between the 2 cohorts. CONCLUSION: We found a significant increase in the number of outpatient shoulder arthroplasty cases being performed at our health institution during the COVID-19 era, likely owing to a multitude of factors including improved perioperative patient management and increased hospital burden from the COVID-19 pandemic. This increase in outpatient cases was associated with a significant reduction in average hospital length of stay and a significant decrease in 90-day readmissions compared with the pre-COVID-19 era. The study data suggest that outpatient TSA can be performed in a safe and efficient manner in the appropriate patient cohort.

Falling "fortresses": Unlocking Governance Entanglements and Shifting Knowledge Paradigms to Counter Climate Change Threats in Biodiversity Conservation.

Biodiversity conservation is facing unprecedented challenges at the intersection of rapidly changing climates, widespread ecosystem degradation under the influence of global warming and resultant human tragedies over livelihood, habitation, adaptation and coping needs. These challenges are more acute across biodiversity hotspots in the Global South. This study disentangles the complex interplay to propose alternative paradigms of governance and policy thinking necessary for sustainable biodiversity conservation. Climate change impacts are exposing critical deficiencies of 'scientific forest management' pursued for over a century. For example, recurrent disasters and ecological shifts are increasingly obfuscating cognitive and physical boundaries between the reserve forest and human habitations; putting additional stress on livelihoods which in turn escalate pressures on the forest commons and fuel further conflicts between conservation governance and local communities. Instead of assisting in adaptation, the existing conservation governance mechanisms are producing further conflicts between humans and non-humans; livelihoods and conservation; disaster management and development. Conducted in the Sundarbans Biosphere Reserve -world's largest mangrove forest ecosystem and a climate change hotspot located along the Bay of Bengal across India and Bangladesh -the study finds an urgent need of rethinking and recalibrating biodiversity conservation in the times of climate change. However, institutional and market-based approaches such as promoting ecotourism or mangrove plantations may have little impact in this regard, the study finds. Instead, integrating cultural ecosystem services and co-producing knowledge will be critical to tackle the entanglements of climate change and its impacts on local lives, livelihoods and biodiversity conservation.

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep-/-) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep-/- mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep-/- mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep-/- mice. In contrast, livers of ShpHep-/- mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.

Organization of directed functional connectivity among nodes of ventral attention network reveals the common network mechanisms underlying saliency processing across distinct spatial and spatio-temporal scales.

Previous neuroimaging studies have extensively evaluated the structural and functional connectivity of the Ventral Attention Network (VAN) and its role in reorienting attention in the presence of a salient (pop-out) stimulus. However, a detailed understanding of the "directed" functional connectivity within the VAN during the process of reorientation remains elusive. Functional magnetic resonance imaging (fMRI) studies have not adequately addressed this issue due to a lack of appropriate temporal resolution required to capture this dynamic process. The present study investigates the neural changes associated with processing salient distractors operating at a slow and a fast time scale using custom-designed experiment involving visual search on static images and dynamic motion tracking, respectively. We recorded high-density scalp electroencephalography (EEG) from healthy human volunteers, obtained saliency-specific behavioral and spectral changes during the tasks, localized the sources underlying the spectral power modulations with individual-specific structural MRI scans, reconstructed the waveforms of the sources and finally, investigated the causal relationships between the sources using spectral Granger-Geweke Causality (GGC). We found that salient stimuli processing, across tasks with varying spatio-temporal complexities, involves a characteristic modulation in the alpha frequency band which is executed primarily by the nodes of the VAN constituting the temporo-parietal junction (TPJ), the insula and the lateral prefrontal cortex (lPFC). The directed functional connectivity results further revealed the presence of bidirectional interactions among prominent nodes of right-lateralized VAN, corresponding only to the trials with saliency. Thus, our study elucidates the invariant network mechanisms for processing saliency in visual attention tasks across diverse time-scales.

Low polyethylene creep and wear following mobile-bearing unicompartmental knee replacement.

PURPOSE: The Oxford unicompartmental knee replacement (UKR) has a fully congruent mobile bearing to minimise wear. However, with younger higher demand patients, wear remains a concern. The aim of this study was to quantify the wear rate of Phase 3 Oxford UKR bearings over the course of 5 years and to identify the factors that influence it. METHODS: 40 medial Oxford UKRs recruited for a randomised study of cemented and cementless fixation were studied with Radiostereometric analysis (RSA) at 1 week, 3 months, 6 months, 1 year, 2 years, and 5 years post-operatively and bearing thickness was calculated. Penetration, defined as the change in thickness compared to the 1-week measurement, was determined. Creep (early penetration) and wear (late penetration at a constant rate) were calculated. The influence of demographic factors, Oxford Knee Score (OKS), Tegner score, fixation and bearing overhang (determined by RSA) on wear was analysed. RESULTS: After 6 months the penetration rate was constant, indicating that wear alone was occurring. The wear rate was 0.07 mm/year (SD 0.03). The creep was 0.06 mm with about 95% occurring during the first 3 months. There was no significant relationship between fixation (cemented/cementless), age, component size, OKS and Tegner score with wear rate. Increasing BMI was associated with decreasing wear (p = 0.042). 37/40 bearings overhung the tibia to some extent and 23/40 overhung the tibia medially. An increase in the area of overhang (p = 0.036), amount of medial overhang (p = 0.028) and distance between the bearing and tibial wall (p = 0.019) were associated with increased wear. Bearings that did not overhang (0.06 mm/year) had less wear (p = 0.025) than those that did (0.08 mm/year). There was no relationship (p = 0.6) between the femoral contact area and wear. CONCLUSION: During the first three to six months after implantation, the bearing becomes 0.06 mm thinner due to creep. The combined wear rate of the upper and lower surfaces of the bearing is constant (0.07 mm/year). The wear is lower if the bearing does not overhang the tibia so surgeons should aim for the bearing to be close to the tibial wall. The orientation of the femoral component does not influence wear. LEVEL OF EVIDENCE: Retrospective Study, Level III.

Utilization of Concurrent Dorsal Root Ganglion Stimulation and Dorsal Column Spinal Cord Stimulation in Complex Regional Pain Syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) can be effectively treated with spinal cord stimulation (t-SCS). There is also evidence that dorsal root ganglion (DRG) stimulation may be superior to t-SCS in CRPS. However, there has been no published data, to our knowledge, that looked at the concurrent use of t-SCS and DRG stimulation for treatment of CRPS. METHODS: Our study includes four patients with severe CRPS who had all been implanted with a t-SCS. While all these patients had positive results from their t-SCS, they all had areas which lacked coverage, giving them incomplete pain relief. These patients also underwent successful trial and implantation of DRG-S. All four patients reported further improvement in their residual pain and function with DRG-S (>60%), and even superior pain relief (>80%) with concurrent use of t-SCS and t-SCS. RESULTS: All patients had a diagnosis of lower extremity CRPS-1. After DRG-S implantation, multiple attempts were made in each patient to use DRG-S alone by temporarily turning the t-SCS off. However, in each attempt, all patients consistently reported superior pain relief and improvement in function with the concurrent use of t-SCS and DRG, as compared to DRG alone. The average numeric rating scale pain score decreased from approximately 7 in the regions not covered by t-SCS to 3 after DRG-S implantation, and to 1.25 with concurrent use t-SCS and DRG-S. CONCLUSION: Both t-SCS and DRG-S have been shown to be effective in treatment of patients with CRPS. In our study, concurrent use of t-SCS and DRG-S provided significant improvement in pain and function as compared to using either device alone. This suggests the potential that combination therapy with t-SCS and DRG-S may be beneficial in patients with CRPS. Further prospective studies are required to evaluate this concept.

A Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Individualized Homeopathic Medicines for Cutaneous Warts.

BACKGROUND: Though frequently used in practice, research studies have shown inconclusive benefits of homeopathy in the treatment of warts. We aimed to assess the feasibility of a future definitive trial, with preliminary assessment of differences between effects of individualized homeopathic (IH) medicines and placebos in treatment of cutaneous warts. METHODS: A double-blind, randomized, placebo-controlled trial (n = 60) was conducted at the dermatology outpatient department of D.N. De Homoeopathic Medical College and Hospital, West Bengal. Patients were randomized to receive either IH (n = 30) or identical-looking placebo (n = 30). Primary outcome measures were numbers and sizes of the warts; secondary outcome was the Dermatology Life Quality Index (DLQI) questionnaire measured at baseline, and every month up to 3 months. Group differences and effect sizes were calculated on the intention-to-treat sample. RESULTS: Attrition rate was 11.6% (IH, 3; placebo, 4). Intra-group changes were significantly greater (all p < 0.05, Friedman tests) in IH than placebo. Inter-group differences were statistically non-significant (all p > 0.05, Mann-Whitney U tests) with small effect sizes-both in the primary outcomes (number of warts after 3 months: IH median [inter-quartile range; IQR] 1 [1, 3] vs. placebo 1 [1, 2]; p = 0.741; size of warts after 3 months: IH 5.6 mm [2.6, 40.2] vs. placebo 6.3 [0.8, 16.7]; p = 0.515) and in the secondary outcomes (DLQI total after 3 months: IH 4.5 [2, 6.2] vs. placebo 4.5 [2.5, 8]; p = 0.935). Thuja occidentalis (28.3%), Natrum muriaticum (10%) and Sulphur (8.3%) were the most frequently prescribed medicines. No harms, homeopathic aggravations, or serious adverse events were reported. CONCLUSION: As regards efficacy, the preliminary study was inconclusive, with a statistically non-significant direction of effect favoring homeopathy. The trial succeeded in showing that an adequately powered definitive trial is both feasible and warranted. TRIAL REGISTRATION: CTRI/2019/10/021659; UTN: U1111-1241-7340.

Epidural Steroid Injections for the Management of Spinal Malignancy-Related Pain: A Pragmatic Review and Retrospective Study.

BACKGROUND: Spinal malignancy-related pain results from tumor, fracture, instability, inflammation, and/or nerve root/spinal cord compression. Systemic corticosteroids are commonly used but have many undesirable adverse effects that impact quality of life and continuation of cancer treatments. Epidural steroid injections (ESIs) may be a viable alternative pain treatment. OBJECTIVES: This study starts with a pragmatic review on the efficacy of ESIs to treat spinal malignancy-related pain. Given the limited evidence, we supplement the study with a single-center, retrospective review. METHODS: A pragmatic review using PRISMA guidelines was conducted in MEDLINE, EMBASE, SCOPUS, and Cochrane Review. Then, a retrospective chart review was performed. RESULTS: A pragmatic review yielded 10 patients who underwent ESI for spinal malignancy-related pain. Three patients had "excellent" relief (≥ 50% relief), who all received thoracic injections. This amounted to level IV evidence and an inconclusive recommendation (Grade C) as per Wright's criteria. In our retrospective review, all thoracic cases achieved at least "moderate" pain improvement (30% to 49% relief). 55.6% had "excellent" relief. Lumbosacral injections resulted in 86.0% with at least "moderate" relief and 69.8% with "excellent" relief. Caudal injections were less likely to benefit than lumbosacral injections (P = 0.02). The transforaminal approach resulted in the best relief. There were no adverse events. CONCLUSIONS: There is inconclusive evidence to use ESIs to treat spinal malignancy-related pain in the current literature. Our retrospective review provides level III evidence for our conclusion that ESIs are safe and efficacious to treat spinal malignancy-related pain. Thoracic/lumbosacral injections led to significantly better pain relief compared with caudal injections.