Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Reducing the stigma surrounding opioid use disorder: evaluating an opioid overdose prevention training program applied to a diverse population.

BACKGROUND: The opioid epidemic is a rapidly growing public health concern in the USA, as the number of overdose deaths continues to increase each year. One strategy for combating the rising number of overdoses is through opioid overdose prevention programs (OOPPs). OBJECTIVE: To evaluate the effectiveness of an innovative OOPP, with changes in knowledge and attitudes serving as the primary outcome measures. METHODS: The OOPP was developed by a group of medical students under guidance from faculty advisors. Training sessions focused on understanding stigmatizing factors of opioid use disorder (OUD), as well as protocols for opioid overdose reversal through naloxone administration. Pre- and post-surveys were partially adapted from the opioid overdose attitudes and knowledge scales and administered to all participants. Paired t-tests were conducted to assess differences between pre- and post-surveys. RESULTS: A total of 440 individuals participated in the training; 381 completed all or the majority of the survey. Participants came from a diverse set of backgrounds, ages, and experiences. All three knowledge questions showed significant improvements. For attitude questions, significant improvements were found in all three questions evaluating confidence, two of three questions assessing attitudes towards overdose reversal, and four of five questions evaluating stigma and attitudes towards individuals with OUD. CONCLUSIONS: Our innovative OOPP was effective not only in increasing knowledge but also in improving attitudes towards overdose reversal and reducing stigma towards individuals with OUD. Given the strong improvements in attitudes towards those with OUD, efforts should be made to incorporate the unique focus on biopsychosocial and sociohistorical components into future OOPPs.

A Comparative Analysis of Online Versus in-Person Opioid Overdose Awareness and Reversal Training for First-Year Medical Students.

INTRODUCTION: Physicians trained in opioid use disorder (OUD) harm reduction can mitigate opioid overdose deaths by prescribing naloxone and educating patients about its use. Unfortunately, many physicians possess OUD stigma. Training during medical school presents an opportunity to reduce OUD stigma and improve opioid overdose reversal knowledge. This study assessed the efficacy of Opioid Overdose Awareness and Reversal Training (OOART) and evaluated the equivalency of the online and in-person OOART. Methods: Voluntary training was delivered to first-year medical (M1) students at one medical school. In 2018 and 2019, 29 and 68 M1 students, respectively, received in-person OOART training and completed pre- and post-training surveys. In 2020, 62 students participated in online OOART training, of which 53 completed both pre- and post-training surveys. Results: All three opioid overdose Knowledge questions showed significant improvements between pre- and post-training survey responses. For Attitude questions, six of eleven questions in 2019 and 2020 and four of eleven questions in 2018 had statistically significant improvements between pre- and post-training survey responses. There were no statistical differences between in-person and online post-training survey results for two out of the three Knowledge questions and all 11 Attitude questions. Conclusions: This study demonstrates that our OOART was effective in increasing opioid overdose reversal knowledge and reducing OUD stigma. There was no meaningful difference in outcomes between the training modalities. These results support the future expansion of online and in-person OOART to a larger population of medical students.

Cosmic Bell Test Using Random Measurement Settings from High-Redshift Quasars.

In this Letter, we present a cosmic Bell experiment with polarization-entangled photons, in which measurement settings were determined based on real-time measurements of the wavelength of photons from high-redshift quasars, whose light was emitted billions of years ago; the experiment simultaneously ensures locality. Assuming fair sampling for all detected photons and that the wavelength of the quasar photons had not been selectively altered or previewed between emission and detection, we observe statistically significant violation of Bell's inequality by 9.3 standard deviations, corresponding to an estimated p value of ≲7.4×10^{-21}. This experiment pushes back to at least ∼7.8 Gyr ago the most recent time by which any local-realist influences could have exploited the "freedom-of-choice" loophole to engineer the observed Bell violation, excluding any such mechanism from 96% of the space-time volume of the past light cone of our experiment, extending from the big bang to today.

Cosmic Bell Test: Measurement Settings from Milky Way Stars.

Bell's theorem states that some predictions of quantum mechanics cannot be reproduced by a local-realist theory. That conflict is expressed by Bell's inequality, which is usually derived under the assumption that there are no statistical correlations between the choices of measurement settings and anything else that can causally affect the measurement outcomes. In previous experiments, this "freedom of choice" was addressed by ensuring that selection of measurement settings via conventional "quantum random number generators" was spacelike separated from the entangled particle creation. This, however, left open the possibility that an unknown cause affected both the setting choices and measurement outcomes as recently as mere microseconds before each experimental trial. Here we report on a new experimental test of Bell's inequality that, for the first time, uses distant astronomical sources as "cosmic setting generators." In our tests with polarization-entangled photons, measurement settings were chosen using real-time observations of Milky Way stars while simultaneously ensuring locality. Assuming fair sampling for all detected photons, and that each stellar photon's color was set at emission, we observe statistically significant ≳7.31σ and ≳11.93σ violations of Bell's inequality with estimated p values of ≲1.8×10^{-13} and ≲4.0×10^{-33}, respectively, thereby pushing back by ∼600 years the most recent time by which any local-realist influences could have engineered the observed Bell violation.

Prospective, Multicenter, Randomized, Double-Blinded, Partial Crossover Study to Assess the Safety and Efficacy of the Novel Neuromodulation System in the Treatment of Patients With Chronic Pain of Peripheral Nerve Origin.

INTRODUCTION: Currently available central nervous system treatment strategies are often insufficient in management of peripheral neuropathic pain, prompting a resurgence of neuromodulation focused on peripheral pain. A new peripheral nerve stimulation device was investigated in a prospective, randomized, double blind, crossover study, looking specifically at efficacy and safety, with Food and Drug Administration oversight. METHODS: Prospective, multicenter, randomized, double-blind, partial crossover study to assess safety and efficacy. After IRB approval, patients were enrolled, implanted, and then followed for three months to assess efficacy and one year for safety based on Food and Drug Administration guidance. RESULTS: One hundred forty-seven patients were consented and screened for the study. Thirty-five did not meet inclusion or exclusion criteria. Ninety-four patients were implanted and then randomized to the treatment (45) or the Control group (49). The primary efficacy endpoint, three months after randomization to treatment, demonstrated that patients receiving active stimulation achieved a statistically significantly higher response rate of 38% vs. the 10% rate found in the Control group (p = 0.0048). Improvement in pain was statistically significant between the randomized groups, with the Treatment group achieving a mean pain reduction of 27.2% from Baseline to Month 3 compared to a 2.3% reduction in the Control group (p < 0.0001). During the partial crossover period, patients again demonstrated statistically significant improvement in pain relief with active stimulation compared to baseline. Further, the Treatment group had significantly better improvement than the Control group in secondary measures including but not limited to quality of life and satisfaction. Safety, assessed throughout the trial and with follow-up to one year, demonstrated no serious adverse events related to the device. All device-related adverse events were minor and self-limiting. CONCLUSION: The novel peripheral nerve stimulation device is a safe and effective treatment strategy to address neuropathic pain of peripheral nerve origin.

Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo controlled study.

PURPOSE: We compared the efficacy and safety of the currently recommended dose of pentosan polysulfate sodium with a third of the daily dose and with placebo. MATERIALS AND METHODS: In this multicenter, double-blind, randomized, placebo controlled study 368 adults with interstitial cystitis/bladder pain syndrome, defined as an ICSI total score of 8 or greater and a score of greater than 0 on the 4 ICSI component items, received pentosan polysulfate sodium 100 mg once daily or 3 times daily, or matching placebo for 24 weeks. Study eligibility was not based on cystoscopy findings. ICSI was administered at baseline, and at weeks 4, 8, 12, 18 and 24. Unblinded interim analysis performed at 6 years with 54% of the target number of 645 patients enrolled resulted in early study termination. RESULTS: There was no statistically significant difference between the pentosan polysulfate sodium group and the placebo group or between the 2 pentosan polysulfate sodium groups for the primary end point, defined as responder achieving a 30% or greater reduction from the baseline ICSI total score at study end. This primary end point was achieved by 48 of 118 patients (40.7%) in the placebo group, and by 51 of 128 (39.8%) and 52 of 122 (42.6%) in the pentosan polysulfate sodium 100 mg once daily and 3 times daily groups, respectively. Pentosan polysulfate sodium was well tolerated with a similar percent of patients (range 10.2% to 13.3%) across the groups discontinuing due to an adverse event. CONCLUSIONS: Results of this study in a broad population of patients with symptoms consistent with interstitial cystitis revealed no treatment effect vs placebo for pentosan polysulfate sodium at the currently established dose or at a third of the daily dose.

Doctor shopping for medications used in the treatment of attention deficit hyperactivity disorder: shoppers often pay in cash and cross state lines.

BACKGROUND: Doctor shopping, defined by filling overlapping prescriptions from more than one prescriber at more than two pharmacies, is a way to obtain scheduled medications for diversion or abuse. Little is known about how far attention deficit hyperactivity disorder (ADHD) medication shoppers travel, how often they cross state lines to fill their ADHD prescriptions and how often they pay for their medication in cash, i.e. entirely out of pocket. OBJECTIVE: We sought to describe the pattern of doctor shopping for ADHD medications: how far shoppers travel, how often they cross state lines to fill their prescriptions, and how often they pay in cash. METHODS: Retrospective cohort study using LRx, a large US retail prescription database. We included subjects with any ADHD medication dispensed between 2011 and 2012. Subjects were followed for 18 months. RESULTS: Of a total of 4 402 464 subjects exposed to ADHD medications, 0.4% developed shopping behavior. Women were more likely to become shoppers. Shoppers travelled a median of 91.9 miles and non-shoppers 0.2 miles to fill their ADHD prescriptions. Almost 28% of the shoppers filled prescriptions in >1 state compared with 4.3% of non-shoppers. Of the shoppers, 27.3% paid at least one prescription in cash compared to 14.4% of the non-shoppers. CONCLUSIONS: Shoppers travelled larger distances, visited more states and paid in cash for ADHD medications more often than non-shoppers. Data sharing among prescriptions monitoring programs can improve their effectiveness and drug utilization studies should take account of cash purchases.

Emergency Department Extremity Radiographs in the Setting of Pain Without Trauma: Are They Worth the Pain?

BACKGROUND: Few data exist that correlate acute radiographic findings of extremity imaging with patients' complaints in the acute care setting. OBJECTIVE: We hypothesize that plain radiographs performed for a complaint of pain in the absence of trauma or signs and symptoms of infection are of low yield. METHODS: We retrospectively analyzed the imaging and charts of 1331 patients who presented to our emergency department (ED) and received extremity radiographs with complaints related to limb trauma, infection, and pain alone. Imaging and outcomes of cases interpreted as positive for acute pathology and those interpreted as indeterminate were analyzed using Fisher's exact tests to evaluate the value of extremity radiographs in the setting of isolated limb pain. RESULTS: Of the patients analyzed, 935 presented with trauma, 234 presented with nontraumatic pain, and 161 presented with signs or symptoms of infection. The rate of definitively positive cases was 30.6% for trauma, 20.6% for infection, and 1.3% for pain. When indeterminate cases were included in the analysis, the rate of acutely positive cases rose to 33.4% for trauma, 28.0% for infection, and 3.0% for pain. Among the three definitively positive pain cases, all three were fractures, none of which resulted in emergent surgery or orthopedic consults. Among the four indeterminately positive pain cases, three proved to be false positives. CONCLUSIONS: Our data suggest that ED imaging of patients presenting with nontraumatic pain is of extremely low yield, resulting in few acute positive findings that require immediate attention in the ED.

Significance of post-traumatic maxillary sinus fluid, or lack of fluid, in a level II trauma population.

Our goal was to test the predictive value of high-attenuation material within the maxillary sinus for adjacent facial bone fracture. After IRB approval, all blunt trauma facial CTs performed over a 5-month period at a level II trauma center were reviewed in consensus by three radiologists for the presence of facial fractures or high attenuation maxillary sinus opacity (≥30HU, ≥40HU, or ≥50HU). Three classes of fractures were analyzed: any fracture, any fracture contiguous with the maxillary sinus, and only fractures not contiguous with the maxillary sinus. Statistics were calculated using two-by-two tables. A total of 844 cases were reviewed with 273 patients having any fracture. There were 402 hemi-faces with any fracture and 62 hemi-faces with fracture contiguous with the maxillary sinus. Sensitivity, specificity, positive predictive value, and negative predictive value for any fracture (using the ≥40HU threshold) were 13, 99, 85, and 78 % respectively; for fracture contiguous with the sinus, these were 71, 99, 72, and 99 % respectively; and for only non-contiguous fractures, these were 2.3, 96, 13, and 80 %, respectively. We conclude that in this level II trauma population, lack of high attenuation maxillary sinus material nearly ruled out fractures in contiguity with the sinus. High-attenuation sinus material is only moderately predictive of a fracture contiguous with the maxillary sinus. Therefore, if after careful review a fracture is not identified, the radiologist should not be overly concerned that a fracture is being missed. High-attenuation sinus material is a poor marker for fractures not contiguous with the maxillary sinus.

Testing Bell's inequality with cosmic photons: closing the setting-independence loophole.

We propose a practical scheme to use photons from causally disconnected cosmic sources to set the detectors in an experimental test of Bell's inequality. In current experiments, with settings determined by quantum random number generators, only a small amount of correlation between detector settings and local hidden variables, established less than a millisecond before each experiment, would suffice to mimic the predictions of quantum mechanics. By setting the detectors using pairs of quasars or patches of the cosmic microwave background, observed violations of Bell's inequality would require any such coordination to have existed for billions of years-an improvement of 20 orders of magnitude.

The Expression and Secretion Profile of TRAP5 Isoforms in Gaucher Disease.

BACKGROUND: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5's two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. METHODS: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. RESULTS: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. CONCLUSIONS: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia-osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD.

ModE-RA: a global monthly paleo-reanalysis of the modern era 1421 to 2008.

The Modern Era Reanalysis (ModE-RA) is a global monthly paleo-reanalysis covering the period between 1421 and 2008. To reconstruct past climate fields an offline data assimilation approach is used, blending together information from an ensemble of transient atmospheric model simulations and observations. In the early period, ModE-RA utilizes natural proxies and documentary data, while from the 17th century onward instrumental measurements are also assimilated. The impact of each observation on the reconstruction is stored in the observation feedback archive, which provides additional information on the input data such as preprocessing steps and the regression-based forward models. The monthly resolved reconstructions include estimates of the most important climate fields. Furthermore, we provide a reconstruction, ModE-RAclim, which together with ModE-RA and the model simulations allows to disentangle the role of observations and model forcings. ModE-RA is best suited to study intra-annual to multi-decadal climate variability and to analyze the causes and mechanisms of past extreme climate events.

Monthly multidisciplinary complex spine conference: a cost-analysis utilizing time-driven activity-based costing.

PURPOSE: To understand costs and provide an initial framework associated with conference implementation as it pertains to complication prevention. METHODS: Team members' time spent on conference preparation, presentation, and follow-up tasks was recorded and averaged to determine the time required to prepare and present one patient. Using 2022 hourly wage rates based on our urban hospital setting, wage values were calculated for each personnel type and applied to their time spent. The total cost of the conference was annualized and calculated from the time spent in the three phases of the conference multiplied by the wage rate. Published data on complication rates and associated costs before and after conference implementation were used to calculate total cost reduction. RESULTS: With 3 active spine surgeons and 108 patients per year, the total time investment was 104.04 min per patient, costing $21,791 annually. Total RN equivalent value per patient was 5.25 for all three phases. Using a historical model, this multidisciplinary approach for adult spinal deformity reduced complications by 51% at 30 days, resulting in cost savings of $418,518 per year. Thus, the model demonstrates that implementation of this approach resulted in a potential total savings of $396,726/year. CONCLUSION: Implementing a cost-saving tool for managing complex spinal disorders is a responsibility of the spine team, who should lead a multidisciplinary conference. The combination of TDABC and lean methodology can effectively demonstrate the variable costs associated with this multidisciplinary effort and models provide evidence of potential cost-savings when applied to a multidisciplinary adult spinal deformity conference. These findings should encourage clinicians and administrators to allocate resources to improve patient care by reducing complications and costs.

Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.

Circulated TGF-ß1 and VEGF-A as Biomarkers for Fabry Disease-Associated Cardiomyopathy.

Fabry disease (FD) is a lysosomal disorder caused by α-galactosidase A deficiency, resulting in the accumulation of globotriaosylceramide (Gb-3) and its metabolite globotriaosylsphingosine (Lyso-Gb-3). Cardiovascular complications and hypertrophic cardiomyopathy (HCM) are the most frequent manifestations of FD. While an echocardiogram and cardiac MRI are clinical tools to assess cardiac involvement, hypertrophic pattern variations and fibrosis make it crucial to identify biomarkers to predict early cardiac outcomes. This study aims to investigate potential biomarkers associated with HCM in FD: transforming growth factor-ß1 (TGF-ß1), TGF-ß active form (a-TGF-ß), vascular endothelial growth factor (VEGF-A), and fibroblast growth factor (FGF2) in 45 patients with FD, categorized into cohorts based on the HCM severity. TGF-ß1, a-TGF-ß, FGF2, and VEGF-A were elevated in FD. While the association of TGF-ß1 with HCM was not gender-related, VEGF was elevated in males with FD and HCM. Female patients with abnormal electrocardiograms but without overt HCM also have elevated TGF-ß1. Lyso-Gb3 is correlated with TGF-ß1, VEGF-A, and a-TGF-ß1. Elevation of TGF-ß1 provides evidence of the chronic inflammatory state as a cause of myocardial fibrosis in FD patients; thus, it is a potential marker of early cardiac fibrosis detected even prior to hypertrophy. TGF-ß1 and VEGF biomarkers may be prognostic indicators of adverse cardiovascular events in FD.

Metasurface-Enabled Holographic Lithography for Impact-Absorbing Nanoarchitected Sheets.

Nanoarchitected materials represent a class of structural meta-materials that utilze nanoscale features to achieve unconventional material properties such as ultralow density and high energy absorption. A dearth of fabrication methods capable of producing architected materials with sub-micrometer resolution over large areas in a scalable manner exists. A fabrication technique is presented that employs holographic patterns generated by laser exposure of phase metasurface masks in negative-tone photoresists to produce 30-40 µm-thick nanoarchitected sheets with 2.1 × 2.4 cm2 lateral dimensions and ≈500 nm-wide struts organized in layered 3D brick-and-mortar-like patterns to result in ≈50-70% porosity. Nanoindentation arrays over the entire sample area reveal the out-of-plane elastic modulus to vary between 300 MPa and 4 GPa, with irrecoverable post-elastic material deformation commencing via individual nanostrut buckling, densification within layers, shearing along perturbation perimeter, and tensile cracking. Laser induced particle impact tests (LIPIT) indicate specific inelastic energy dissipation of 0.51-2.61 MJ kg-1 , which is comparable to other high impact energy absorbing composites and nanomaterials, such as Kevlar/poly(vinyl butyral) (PVB) composite, polystyrene, and pyrolized carbon nanolattices with 23% relative density. These results demonstrate that holographic lithography offers a promising platform for scalable manufacturing of nanoarchitected materials with impact resistant capabilities.

Clinical Guidelines for the Evaluation and Treatment of Lumbar Disc Herniations: How Accurate is the Internet?

OBJECTIVE: To compare information online regarding lumbar disc herniation (LDH) on commonly searched websites and compare those findings with the evidence-based recommendations listed in the North American Spine Society (NASS) clinical practice guidelines. METHODS: NASS Clinical Practice Guidelines, Internet searches were performed utilizing three common search engines (Google, Bing, Yahoo) and keywords associated with LDH. The top 20 websites from each search were selected. The content regarding diagnosis and treatment of LDH was compared to the NASS clinical practice guidelines. RESULTS: On average, websites mentioned only 59% of recommendations supported by Level I evidence. Websites included an average of 3 recommendations not discussed in the NASS guidelines out of an average of 12 total recommendations. Muscle and sensory testing and physical therapy were the most frequent recommendations, appearing on over 80% of websites. Websites were equally likely to contain recommendations backed by high-quality evidence as recommendations not included in NASS guidelines. CONCLUSIONS: This study demonstrates that websites regarding LDH contain a mix of information, with only a fraction of recommendations aligning with NASS clinical guidelines. Patients who use these websites are presented with unsubstantiated information, conceivably impacting their understanding, expectations and decision-making in physician offices.

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease.

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

Identification and Characterization of a Novel Species of Genus Akkermansia with Metabolic Health Effects in a Diet-Induced Obesity Mouse Model.

Akkermansia muciniphila is a well-known bacterium with the ability to degrade mucin. This metabolic capability is believed to play an important role in the colonization of this bacterium in the gut. In this study, we report the identification and characterization of a novel Akkermansia sp. DSM 33459 isolated from human feces of a healthy donor. Phylogenetic analysis based on the genome-wide average nucleotide identity indicated that the Akkermansia sp. DSM 33459 has only 87.5% similarity with the type strain A. muciniphila ATCC BAA-835. Akkermansia sp. DSM 33459 showed significant differences in its fatty acid profile and carbon utilization as compared to the type strain. The Akkermansia sp. DSM 33459 strain was tested in a preclinical obesity model to determine its effect on metabolic markers. Akkermansia sp. DSM 33459 showed significant improvement in body weight, total fat weight, and resistin and insulin levels. Interestingly, these effects were more pronounced with the live form as compared to a pasteurized form of the strain. The strain showed production of agmatine, suggesting a potential novel mechanism for supporting metabolic and cognitive health. Based on its phenotypic features and phylogenetic position, it is proposed that this isolate represents a novel species in the genus Akkermansia and a promising therapeutic candidate for the management of metabolic diseases.