Flexing with lignin: lignin-based elastomers synthesised from untreated kraft black liquor.

The synthesis and characterisation of a lignin-based elastomer system using lignin-epoxy-resins is presented. Untreated kraft black liquor was used to synthesise glycidyl lignin or black liquor-based epoxy resin (BLER), following a published procedure. A flexible, elastomeric thermoset was produced by cross-linking BLER with succinic anhydride (SA). The produced material was characterised in respect to its chemical, thermal, mechanical and swelling characteristics. In addition, vertical burning tests were performed. The obtained lignin-based elastomeric thermoset had a tensile strength of 1.0 ± 0.20 MPa and elastic moduli of 1.6 ± 1.4 and 0.44 ± 0.35 MPa at 5% and 50% elongation, respectively. A maximum elongation of 151 ± 49% was found.

Skin color reporting in basal cell carcinoma-related randomized controlled trials in top dermatology journals: a systematic review.

OBJECTIVES: To determine the rate skin color is reported in randomized controlled trials (RCTs) involving basal cell carcinoma (BCC) identification and treatment in the top ten dermatology journals. METHODS: A systematic review was conducted of RCTs involving BCC among the top ten dermatology journals, determined by impact factor, from inception to July 11th, 2023. Studies were included if they reviewed the prevention, detection, and treatment of BCC, directly involved patients, and were classified as RCTs. Studies were classified as positive for reporting skin of color (SOC) if the demographic data in the methods or results included any of the following terms: Fitzpatrick scale, race, ethnicity, skin of color, or sunburn tendency. RESULTS: Of the 51 studies identified, only 23 articles reported data pertaining to skin color within the results section (45.1%); whereas 28 articles mentioned skin color somewhere within the text (54.9%). Subgroup analysis was performed, and no statistical significance was found for study location or year of publication. CONCLUSION: Dark skin color can make it more difficult to diagnose skin tumors and it is unknown if race affects response to treatment. Less than 50% of RCTs related to basal cell carcinoma in top international dermatology journals included skin color within the demographic portion of their results section pertaining to study participants. Subgroup analysis demonstrated that studies performed within the United States reported skin color less than half the time (40%). Additionally, there has been no statistically significant difference in reporting over the past 4 decades. Further research is necessary to determine whether low reporting rates of race/skin color in BCC-related RCTS could impact diagnostic or treatment recommendations for patient care in this group.

The Concealment of Health Information at the Intersection of Sexual Orientation and Race.

Purpose: Sexually and racially minoritized people often have mistrust toward the healthcare system due to both perceived and actual experiences of discrimination. This may result in increased privacy concerns and a reluctance to share health-related information with health care providers. Drawing upon minority stress and an intersectionality framework, this study examines how rates of concealing health information differ between non-Hispanic White heterosexual people, non-Hispanic White lesbian, gay, and bisexual (LGB) people, racially minoritized heterosexual people, and those who are both sexually and racially minoritized. Methods: Using nationally representative cross-sectional data from the Health Information National Trends Survey from 2017 and 2018 (n = 4575), we fit logistic regression models to examine (1) whether sexually and racially minoritized people conceal health information from their providers more than their counterparts and (2) whether this tendency increases for those with multiple marginalized identities. Furthermore, we fit linear regression models to examine whether and how concealing health information from providers are linked to health outcomes. Results: Sexually and racially minoritized people had higher odds of concealing health information from providers than their counterparts. Those with multiple marginalized identities had even higher odds of withholding health information than other groups. Finally, we found a significant negative association between concealing health information and mental health. Conclusion: Our findings underscore the need to consider how the intersection of multiple marginalized identities shape health experiences and concerns over privacy in health care matters. We call for further research to better understand the complex dynamics of patient-provider relationships for marginalized populations.

Unexpected Low Rate of Amyloid-ß Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024.

Ventrointermediate thalamic stimulation improves motor learning in humans.

Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a repeated sequence. These results highlight the role of thalamo-cortical activity in motor learning.

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

Bayesian Estimation Improves Prediction of Outcomes after Epilepsy Surgery.

Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We quantified the statistical power and magnitude error of studies of epilepsy surgery outcomes. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4 (median odds ratio 9.3 vs. median true odds ratio 1.7), while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6 (2.7 vs. 1.7). We conclude that Bayesian estimation of odds ratio attenuates the exaggeration of significant effect sizes in underpowered studies. This approach could help improve patient counseling about the chance of seizure freedom after epilepsy surgery.

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Signaling through the nicotinic acetylcholine receptor in the liver protects against the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of liver steatosis, the most common liver disease, and substantially increases the mortality rate. However, limited therapies are currently available to prevent MASH development. Identifying potential pharmacological treatments for the condition has been hampered by its heterogeneous and complex nature. Here, we identified a hepatic nonneuronal cholinergic signaling pathway required for metabolic adaptation to caloric overload. We found that cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) is highly expressed in hepatocytes of mice and humans. Further, CHRNA2 is activated by a subpopulation of local acetylcholine-producing macrophages during MASH development. The activation of CHRNA2 coordinates defensive programs against a broad spectrum of MASH-related pathogenesis, including steatosis, inflammation, and fibrosis. Hepatocyte-specific loss of CHRNA2 signaling accelerates the disease onset in different MASH mouse models. Activation of this pathway via pharmacological inhibition of acetylcholine degradation protects against MASH development. Our study uncovers a hepatic nicotinic cholinergic receptor pathway that constitutes a cell-autonomous self-defense route against prolonged metabolic stress and holds therapeutic potential for combatting human MASH.

BRCA status dictates Wnt responsiveness in epithelial ovarian cancer.

The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2 mutant (BRCA2mt) patients are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 function in ovarian cancer. Transcriptomic and pathway analysis comparing BRCA1 mutant (BRCA1mt), BRCA2mt and homologous recombination wild-type (HRwt) ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type (BRCAwt), BRCA1null and BRCA2null mouse ovarian cancer cells, we observed preferential activation of the canonical Wnt/ß-catenin signaling in BRCAwt ovarian cancer cells while the non-canonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1null cells. Interestingly, BRCA2null mouse ovarian cancer cells, demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor, Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival.

Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger-Ellison Syndrome (ZES) Patients.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Occult residual ovarian tissue at the time of minimally invasive risk reducing surgery in women with BRCA mutations.

OBJECTIVE: To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. METHODS: A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. RESULTS: Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. CONCLUSION: In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.

hTERT Epigenetics Provides New Perspectives for Diagnosis and Evidence-Based Guidance of Chemotherapy in Cancer.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

Acquisitions of behavioral health treatment facilities from 2010 to 2021.

Private equity (PE) and other for-profit ownership of behavioral health (mental health and substance use) treatment facilities have become increasingly prevalent, but data on these acquisitions are not readily available. In this study, we describe a novel database that contains information on the universe of behavioral health acquisitions that occurred between 2010 and 2021. We found that the frequency of behavioral health facilities involved in acquisitions increased substantially, from 32 facilities in 2010 to 1330 in 2021. The total number of facilities involved in acquisitions was 2806. Most of these facilities provided outpatient services only (N = 2073) and offered only mental health services (N = 1428). Private equity-backed acquisitions accounted for around 60% of all acquisition activity (N = 1678 facilities PE, N = 1128 facilities other for-profit). 25% of acquired facilities were located within 20 miles of one another (N = 561), 50% occurred within 80 miles (N = 1403), and 75% occurred within 319 miles (N = 2104). Future research should evaluate the effects of this consolidation on behavioral healthcare access, quality, spending, and patient outcomes.

Clinical Reasoning: A 17-Year-Old Adolescent Boy With New Altered Mental Status in the Pediatric Intensive Care Unit.

We present the case of a 17-year-old adolescent boy admitted to the Pediatric Intensive Care Unit with an extensive necrotizing soft tissue infection who subsequently developed altered mental status and autonomic instability. Altered mental status is a common occurrence in critically ill children with a broad differential of etiologies. After ruling out organic causes of encephalopathy, management is typically focused on avoiding deliriogenic agents, including benzodiazepines. Dopamine antagonist medications may also be administered adjunctively to manage agitation or delirium that is refractory to other measures. We review the workup and differential diagnosis for altered mentation in critically ill children and discuss the current understanding of a rare etiology of altered mental status in the pediatric population.

Symptomatic Radial-Sided Tears of the Triangular Fibrocartilage Complex: An All-Arthroscopic Repair Using Bone Anchors.

Radial-sided tears of the triangular fibrocartilage, though uncommon, can still be a reason for ulnar-sided wrist pain, and, at times, instability of the distal radioulnar joint. Historically, it has been believed that because of the paucity of vascularity along the radial edge of the triangular fibrocartilage complex (TFCC), any form of repair will not lead to healing, thus stating it to be an exercise in futility. Current literature deftly argues against this previously prevailing concept and supports the need of repair in case of symptomatic radial-sided TFCC tears. In our study, we describe an all-arthroscopic technique of repairing radial-sided tears using a bone anchor which can be a fast and simple procedure in the hands of an orthopaedic or hand surgeon trained in arthroscopy. This technique also circumvents the risk of injuring the superficial radial nerve and other radial-sided structures which are stated complications of the current arthroscopic repairs.

Ideal strategy for nonvariceal upper gastrointestinal bleeding.

PURPOSE OF REVIEW: Over 300 000 hospital admissions in the United States each year are due to patients with upper gastrointestinal (GI) bleeding (UGIB). Common etiologies of nonvariceal UGIB include peptic ulcers, mucosal erosions of the esophagus, stomach or duodenum, Mallory-Weiss tears, Dieulafoy lesions, upper GI tract malignancy, or other etiology. RECENT FINDINGS: Peptic ulcers classified as Forrest Ia, Ib, or IIa require endoscopic hemostasis, while IIb ulcers may be considered for endoscopic clot removal with endoscopic treatment of any underlying major stigmata. Endoscopic hemostasis for ulcers classified as Forrest IIc or III is not advised due to the low risk of recurrent bleeding. Endoscopic hemostasis in ulcer bleeding can be achieved using injection, thermal, and/or mechanical modalities. SUMMARY: This review focuses on the currently recommended endoscopic therapies of patients presenting with acute nonvariceal upper gastrointestinal hemorrhage.