Higher ultraviolet light exposure is associated with lower mortality: An analysis of data from the UK biobank cohort study.

We aimed to examine associations between ultraviolet (UV) exposure and mortality among older adults in the United Kingdom (UK). We used data from UK Biobank participants with two UV exposures, validated with measured vitamin D levels: solarium use and annual average residential shortwave radiation. Associations between the UV exposures, all-cause and cause-specific mortality were examined as adjusted hazard ratios. The UV exposures were inversely associated with all-cause, cardiovascular disease (CVD) and cancer mortality. Solarium users were also at a lower risk of non-CVD/non-cancer mortality. The benefits of UV exposure may outweigh the risks in low-sunlight countries.

Immunogenicity of a peptide-based vaccine for measles: a pilot evaluation in a mouse model.

Although neutralizing antibody is an established correlate of protection for measles, T cell-mediated responses play at least two critical roles in immunity to measles: first, through provision of 'help' enabling robust humoral immune responses; and second, through clearance of measles virus-infected cells. Previously, we identified 13 measles-derived peptides that bound to human leukocyte antigen (HLA) molecules in Priess cells infected with measles virus. In this study, we evaluated the immunogenicity of these peptides in a transgenic mouse model. Our results demonstrated that these peptides induced Th1-biased immune responses at varying levels. Of the 13 peptides, the top four immunogenic peptides were further selected for a viral challenge study in mice. A vaccine based on a combination of these four peptides reduced morbidity and weight loss after viral challenge compared to placebo. Our results emphasize the potential of T cell-mediated, peptide-based vaccines against measles.

Ligamentum teres lesions are associated with compositional and structural hip cartilage degenerative change: region-specific cartilage degeneration.

OBJECTIVES: To investigate the association between magnetic resonance imaging (MRI)-based ligamentum teres lesions (LTL) and structural hip degeneration. METHODS: Bilateral 3-T hip MRIs of participants (n = 93 [36 men]; mean age ( ± SD) 51 years ± 15.4) recruited from the community and the orthopedic clinic of a single medical center were included. Clinical and imaging data acquired included hip disability and osteoarthritis outcome scores, semi-quantitative scoring of hip osteoarthritis on MRI (SHOMRI) scores on fluid-sensitive sequences, and cartilage T1ρ/T2 compositional sequences. An MRI-based LTL scoring system, incorporating continuity, thickening, and signal intensity, ranging from 0 (normal) to 4 (complete tear) was constructed. Hip morphological features associated with LTL, based on functional or anatomical relationships to LT, were defined. Relationships between MRI-LT scores and SHOMRI, global/regional cartilage T1ρ/T2, and proposed morphological abnormalities and LTL were explored by mixed effects linear and logistic regression models. RESULTS: In 82 (46.1%) hips, no pain was documented; 118 (63.4%) and 68 (36.6%) hips were graded as KL-grade ≤ 1 and ≥ 2, respectively. Compared to MRI-LT score = 0 (normal), score = 4 (complete tear) revealed significantly worse subchondral bony degenerative changes for bone marrow lesions (SHOMRI-BML) and subchondral cysts (SHOMRI-sc) (p < 0.001, p = 0.015, respectively). Global acetabular T1ρ, femoral T2 were significantly increased for abnormal MRI-LT scores (p-range = 0.005-0.032). Regional analyses revealed significantly increased T1ρ/T2 in central acetabular/increased T2 in off-central femoral regions (p-range = 0.005-0.046). Pulvinar effusion-synovitis, shallow fovea, and foveal osteophytes were significantly associated with abnormal LT MRI findings (p-range = < 0.001-0.044). CONCLUSION: MRI abnormalities of LT are associated with worse SHOMRI-sc/BML scores, indicative of hip osteoarthritis and higher T1ρ and T2 that differ by region. Pulvinar effusion-synovitis and changes in femoral head morphology are associated with LTL. CLINICAL RELEVANCE STATEMENT: Abnormal ligamentum teres findings identified via MRI are associated with structural degenerative changes of the hip joint and alterations in acetabular and femoral cartilage compositions show spatial differences in relation to LTL. KEY POINTS: The clinical significance of common ligamentum teres lesions (LTL) on MRI is not well understood. LTL identified by an MRI-based scoring system is associated with worse biomarkers, indicating more advanced degenerative hip changes. Effusion-synovitis signal at pulvinar, shallow fovea capitis, and foveal osteophytes are associated with LTL on imaging.

Heart Failure Risk Prediction in a Population With a High Burden of Diabetes: Evidence From the Strong Heart Study.

BACKGROUND: Despite the high burden of diabetes and cardiovascular risk factors in American Indian communities in the United States, prospective studies of heart failure (HF) in this population group are scarce, and the generalizability of previous HF risk scales may be limited. We developed a parsimonious HF risk prediction equation that accounts for relevant risk factors affecting American Indian communities, focusing on diabetes and kidney damage. METHODS AND RESULTS: A total of 3059 participants from the SHS (Strong Heart Study) (56±8 years of age, 58% women) were included. Five hundred seven developed HF. Progressively adjusted Cox proportional hazards models were used to identify risk factors for HF and HF subtypes. Predictors of risk at 5 and 10 years included older age (hazard ratio [HR], 1.79 [95% CI, 1.43-2.25]; HR, 1.68 [95% CI, 1.44-1.95]), smoking (HR, 2.26 [95% CI, 1.23-4.13]; HR, 2.08 [95% CI, 1.41-3.06]), macroalbuminuria (HR, 8.38 [95% CI, 4.44-15.83]; HR, 5.20 [95% CI, 3.42-7.9]), microalbuminuria (HR, 2.72 [95% CI, 1.51-4.90]; HR, 1.92 [95% CI, 1.33, 2.78]), and previous myocardial infarction (HR, 6.58 [95% CI, 2.54-17.03]; HR, 3.87 [95% CI, 2.29-6.54]), respectively. These predictors, together with diabetes diagnosis and glycated hemoglobin were significant at 10 and 28 years. High discrimination performance was achieved (C index, 0.81 [95% CI, 0.76-0.84]; C index, 0.78 [95% CI, 0.75-0.81]; and C index, 0.77 [95% CI, 0.74-0.78] at 5, 10, and up to 28 years of follow up, respectively). Some associations varied across HF subtypes, although diabetes, albuminuria, and previous myocardial infarction were associated with all subtypes. CONCLUSIONS: This prospective study of HF risk factors in American Indian communities identifies that smoking, body mass index, and indicators of diabetes control and kidney damage (glycated hemoglobin and albuminuria) are major determinants of HF. Our findings can improve HF risk assessment in populations with a high burden of diabetes.

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Comparative Effectiveness of Bimekizumab and Ustekinumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.

INTRODUCTION: A matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy at 52 weeks (Wk52) of bimekizumab 160 mg every 4 weeks (Q4W) and ustekinumab 45 or 90 mg every 12 weeks (Q12W) in patients with psoriatic arthritis (PsA) who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or who had a previous inadequate response or an intolerance to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Relevant trials were systematically identified. Individual patient data from the bimekizumab trials BE OPTIMAL (NCT03895203; N = 431) and BE COMPLETE (NCT03896581; N = 267) were matched with summary data on patients receiving ustekinumab in the PSUMMIT 1 trial (NCT01009086; 45 mg, N = 205; 90 mg; N = 204) and a subgroup of TNFi-IR patients receiving ustekinumab in the PSUMMIT 2 trial (NCT01077362; 45 mg, N = 60; 90 mg, N = 58), respectively. Patients from the bimekizumab trials were re-weighted using propensity scores to match the baseline characteristics of the ustekinumab trial patients. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Non-placebo-adjusted comparisons of recalculated bimekizumab and ustekinumab outcomes for the American College of Rheumatology (ACR) 20/50/70 response criteria (non-responder imputation) were analyzed. RESULTS: In patients who were bDMARD naïve, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (odds ratio [95% confidence interval] 45 mg: 2.14 [1.35, 3.40]; 90 mg: 1.98 [1.24, 3.16]), ACR50 (45 mg: 2.74 [1.75, 4.29]; 90 mg: 2.29 [1.48, 3.55]), and ACR70 (45 mg: 3.33 [2.04, 5.46]; 90 mg: 3.05 [1.89, 4.91]). In patients who were TNFi-IR, bimekizumab had a greater likelihood of response than ustekinumab at Wk52 for ACR20 (45 mg: 4.17 [2.13, 8.16]; 90 mg: 4.19 [2.07, 8.49]), ACR50 (45 mg: 5.00 [2.26, 11.05]; 90 mg: 3.86 [1.70, 8.79]), and ACR70 (45 mg: 9.85 [2.79, 34.79]; 90 mg: 6.29 [1.98, 20.04]). CONCLUSIONS: Using MAIC, bimekizumab showed greater efficacy than ustekinumab in achieving all ACR responses in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. TRIAL REGISTRATION: NCT03895203, NCT03896581, NCT01009086, NCT01077362.

Comparative Effectiveness of Bimekizumab and Risankizumab in Patients with Psoriatic Arthritis at 52 Weeks Assessed Using a Matching-Adjusted Indirect Comparison.

INTRODUCTION: The relative efficacy of bimekizumab and risankizumab in patients with PsA who were biologic disease-modifying anti-rheumatic drug naïve (bDMARD naïve) or with previous inadequate response or intolerance to tumor necrosis factor inhibitors (TNFi-IR) was assessed at 52 weeks (Wk52) using matching-adjusted indirect comparisons (MAIC). METHODS: Relevant trials were systematically identified. For patients who were bDMARD naïve, individual patient data (IPD) from BE OPTIMAL (NCT03895203; N = 431) were matched with summary data from KEEPsAKE-1 (NCT03675308; N = 483). For patients who were TNFi-IR, IPD from BE COMPLETE (NCT03896581; N = 267) were matched with summary data from the TNFi-IR patient subgroup in KEEPsAKE-2 (NCT03671148; N = 106). To adjust for cross-trial differences, patients from the bimekizumab trials were re-weighted to match the baseline characteristics of patients in the risankizumab trials. Adjustment variables were selected based on expert consensus (n = 5) and adherence to established MAIC guidelines. Recalculated bimekizumab Wk52 outcomes for American College of Rheumatology (ACR) 20/50/70 response criteria and minimal disease activity (MDA) index (non-responder imputation) were compared with risankizumab outcomes via non-placebo-adjusted comparisons. RESULTS: In patients who were bDMARD naïve, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR50 (odds ratio [95% confidence interval]: 1.52 [1.11, 2.09]) and ACR70 (1.80 [1.29, 2.51]). In patients who were TNFi-IR, bimekizumab had a significantly greater likelihood of response than risankizumab at Wk52 for ACR20 (1.78 [1.08, 2.96]), ACR50 (3.05 [1.74, 5.32]), ACR70 (3.69 [1.82, 7.46]), and MDA (2.43 [1.37, 4.32]). CONCLUSIONS: Using MAIC, bimekizumab demonstrated a greater likelihood of efficacy in most ACR and MDA outcomes than risankizumab in patients with PsA who were bDMARD naïve and TNFi-IR at Wk52. TRIAL REGISTRATION: NCT03895203, NCT03896581, NCT03675308, NCT03671148.

Efficacy and Safety of Bimekizumab in Patients With Psoriatic Arthritis With or Without Methotrexate: 52-Week Results From Two Phase 3 Studies.

OBJECTIVE: The objective of this study was to assess 52-week efficacy and safety of bimekizumab in patients with active psoriatic arthritis (PsA) with or without concomitant methotrexate (+/-MTX) treatment at baseline. METHODS: We conducted a post hoc analysis of patients in BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve), BE COMPLETE (NCT03896581; prior inadequate response or intolerance to tumor necrosis factor inhibitors [TNFi-IR]), and the BE VITAL open-label extension (NCT04009499) study. Patients were randomized to one of the following treatment groups: bimekizumab 160 mg every four weeks, placebo, or a reference drug (adalimumab 40 mg every two weeks; BE OPTIMAL only). From Week 16, placebo-randomized patients received bimekizumab. Missing data were imputed using non-responder imputation, multiple imputation, or worst-category imputation. RESULTS: Through Week 52, similar proportions of bimekizumab-treated patients achieved American College of Rheumatology 50% (ACR50) response criteria for both +MTX and -MTX (BE OPTIMAL: 54.4% +MTX, 54.7% -MTX; BE COMPLETE: 56.3% +MTX, 48.0% -MTX). Similar proportions of bimekizumab-treated patients achieved complete skin clearance (Psoriasis Area and Severity Index 100% [PASI100] response) and minimal disease activity in both +MTX and -MTX groups. Similar trends were seen in placebo/bimekizumab-treated patients. Through Week 52, the proportion of bimekizumab-treated patients with ≥1 treatment-emergent adverse event were similar between the +MTX and -MTX groups (BE OPTIMAL 325 of 410 [79.3%] vs 230 of 292 [78.8%], BE COMPLETE 105 of 168 [62.5%] vs 138 of 220 [62.7%]). The safety profile was comparable between subgroups and consistent with the prior safety profile of bimekizumab. CONCLUSION: Treatment with bimekizumab demonstrated consistent, sustained efficacy to 52 weeks in bDMARD-naïve and TNFi-IR patients with PsA and was well tolerated, irrespective of concomitant MTX.

Preclinical studies of RA475, a guanidine-substituted spirocyclic candidate RPN13/ADRM1 inhibitor for treatment of ovarian cancer.

There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin.

Preoperative Crohn's Disease Exclusion Diet and Exclusive Enteral Nutrition in Adults with Crohn's Disease: A Feasibility Randomised Controlled Trial.

Preoperative exclusive enteral nutrition (EEN) improves nutritional status, reduces intestinal inflammation, and likely improves surgical outcomes. Crohn's disease exclusion diet with partial enteral nutrition (CDED) also reduces intestinal inflammation but its safety preoperatively is unknown. This single-blinded, multicentre, randomised controlled trial of three preoperative nutritional therapies aimed to assess the feasibility of recruiting and retaining patients and collecting primary and secondary effectiveness outcomes. Adults undergoing elective Crohn's disease surgery with a body mass index (BMI) > 18.5 kg/m2 and without significant weight loss were eligible to participate. Patients were randomly assigned to six weeks of preoperative EEN, CDED, or standard care. Feasibility, nutritional, radiological, and surgical outcomes were recorded. Over 18 months, 48 patients were screened, 17 (35%) were randomised, and 13/17 (76%) patients were retained in the intervention phase. It was feasible to collect primary and secondary effectiveness data; at day 30, three patients had Clavien Dindo Grade 2 complications, and 10 had no complications. Nutritional therapy adherence of patients retained in the study was high. Recruitment and retention of patients who need elective Crohn's disease surgery for preoperative nutritional therapy is possible, although a shorter duration may improve EEN completion. The impact on surgical outcomes should be assessed in a larger study.

Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.

Tamoxifen is an important antiestrogen for the treatment of hormone receptor-positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6-mediated metabolism to 4-OH-solanidine (m/z 414) and 3,4-seco-solanidine-3,4-dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4-OH-solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4-OH-solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4-OH-solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4-OH-solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4-OH-solanidine, and SSDA are diet-derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

Prior traumatic brain injury is a risk factor for in-hospital mortality in moderate to severe traumatic brain injury: a TRACK-TBI cohort study.

Objectives: An estimated 14-23% of patients with traumatic brain injury (TBI) incur multiple lifetime TBIs. The relationship between prior TBI and outcomes in patients with moderate to severe TBI (msTBI) is not well delineated. We examined the associations between prior TBI, in-hospital mortality, and outcomes up to 12 months after injury in a prospective US msTBI cohort. Methods: Data from hospitalized subjects with Glasgow Coma Scale score of 3-12 were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (enrollment period: 2014-2019). Prior TBI with amnesia or alteration of consciousness was assessed using the Ohio State University TBI Identification Method. Competing risk regressions adjusting for age, sex, psychiatric history, cranial injury and extracranial injury severity examined the associations between prior TBI and in-hospital mortality, with hospital discharged alive as the competing risk. Adjusted HRs (aHR (95% CI)) were reported. Multivariable logistic regressions assessed the associations between prior TBI, mortality, and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-3 (vs. 4-8)) at 3, 6, and 12 months after injury. Results: Of 405 acute msTBI subjects, 21.5% had prior TBI, which was associated with male sex (87.4% vs. 77.0%, p=0.037) and psychiatric history (34.5% vs. 20.7%, p=0.010). In-hospital mortality was 10.1% (prior TBI: 17.2%, no prior TBI: 8.2%, p=0.025). Competing risk regressions indicated that prior TBI was associated with likelihood of in-hospital mortality (aHR=2.06 (1.01-4.22)), but not with hospital discharged alive. Prior TBI was not associated with mortality or unfavorable outcomes at 3, 6, and 12 months. Conclusions: After acute msTBI, prior TBI history is independently associated with in-hospital mortality but not with mortality or unfavorable outcomes within 12 months after injury. This selective association underscores the importance of collecting standardized prior TBI history data early after acute hospitalization to inform risk stratification. Prospective validation studies are needed. Level of evidence: IV. Trial registration number: NCT02119182.

Evaluating the Accuracy of ChatGPT in Common Patient Questions Regarding HPV+ Oropharyngeal Carcinoma.

OBJECTIVES: Large language model (LLM)-based chatbots such as ChatGPT have been publicly available and increasingly utilized by the general public since late 2022. This study sought to investigate ChatGPT responses to common patient questions regarding Human Papilloma Virus (HPV) positive oropharyngeal cancer (OPC). METHODS: This was a prospective, multi-institutional study, with data collected from high volume institutions that perform >50 transoral robotic surgery cases per year. The 100 most recent discussion threads including the term "HPV" on the American Cancer Society's Cancer Survivors Network's Head and Neck Cancer public discussion board were reviewed. The 11 most common questions were serially queried to ChatGPT 3.5; answers were recorded. A survey was distributed to fellowship trained head and neck oncologic surgeons at 3 institutions to evaluate the responses. RESULTS: A total of 8 surgeons participated in the study. For questions regarding HPV contraction and transmission, ChatGPT answers were scored as clinically accurate and aligned with consensus in the head and neck surgical oncology community 84.4% and 90.6% of the time, respectively. For questions involving treatment of HPV+ OPC, ChatGPT was clinically accurate and aligned with consensus 87.5% and 91.7% of the time, respectively. For questions regarding the HPV vaccine, ChatGPT was clinically accurate and aligned with consensus 62.5% and 75% of the time, respectively. When asked about circulating tumor DNA testing, only 12.5% of surgeons thought responses were accurate or consistent with consensus. CONCLUSION: ChatGPT 3.5 performed poorly with questions involving evolving therapies and diagnostics-thus, caution should be used when using a platform like ChatGPT 3.5 to assess use of advanced technology. Patients should be counseled on the importance of consulting their surgeons to receive accurate and up to date recommendations, and use LLM's to augment their understanding of these important health-related topics.

Norepinephrine Neurons in the Nucleus of the Solitary Tract Suppress Luteinizing Hormone Secretion in Female Mice.

Stress impairs fertility, at least in part, via inhibition of gonadotropin secretion. Luteinizing hormone (LH) is an important gonadotropin that is released in a pulsatile pattern in males and in females throughout the majority of the ovarian cycle. Several models of stress, including acute metabolic stress, suppress LH pulses via inhibition of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy cells) which form the pulse generator. The mechanism for inhibition of KNDy neurons during stress, however, remains a significant outstanding question. Here, we investigated a population of catecholamine neurons in the nucleus of the solitary tract (NTS), marked by expression of the enzyme dopamine beta-hydroxylase (DBH), in female mice. First, we found that a subpopulation of DBH neurons in the NTS is activated (express c-Fos) during metabolic stress. Then, using chemogenetics, we determined that activation of these cells is sufficient to suppress LH pulses, augment corticosterone secretion, and induce sickness-like behavior. In subsequent studies, we identified evidence for suppression of KNDy cells (rather than downstream signaling pathways) and determined that the suppression of LH pulses was not dependent on the acute rise in glucocorticoids. Together these data support the hypothesis that DBH cells in the NTS are important for regulation of neuroendocrine and behavioral responses to stress.

Chemical Standardization of Milk Thistle (Silybum marianum L.) Extract Using UHPLC-MS/MS and the Method of Standard Addition.

Extracts prepared from the seeds of the medicinal plant milk thistle [Silybum marianum (L.) Gaertn. (Asteraceae)] are widely used as dietary supplements due to anti-inflammatory, antitumor, and hepatoprotective effects. Called silymarin, the main components of lipophilic extracts of milk thistle seeds are flavonoids and flavonolignans including silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, taxifolin, and 2,3-dehydrosilybins. The aim of this study was to develop a method based on UHPLC-MS/MS for the chemical authentication and standardization of milk thistle silymarin. Validation included the method of standard addition to account for the lack of a blank matrix. Potential matrix effects were investigated by analyzing silymarin standards dissolved only in the initial UHPLC mobile phase. Measurements of six flavonolignans and taxifolin in the milk thistle extract using UHPLC-MS/MS with standard addition or external standard calibration produced similar results for all analytes except silydianin and 2,3-dehydrosilybin B, which showed significant peak enhancement during negative ion electrospray due to botanical matrix effects. The UHPLC-MS/MS-based method of standard addition requires <10 min per injection and is suitable for the standardization of silymarin from milk thistle in support of preclinical and clinical studies of safety and efficacy.

Dopamine D1 Receptor Agonists Rescue Age-related Decline in Temporal Order Memory.

Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.

Precision-guided treatment in high-risk pediatric cancers.

Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.

Impact of CYP2C19 metabolizer status on esophageal mucosal inflammation, acid exposure, and motility among patients on chronic proton-pump inhibitor therapy with refractory symptoms of gastroesophageal reflux disease.

Background: The extent of disease severity remains unclear among CYP2C19 rapid and ultra-rapid metabolizers with refractory symptoms of gastroesophageal reflux disease (GERD) on chronic proton-pump inhibitors (PPIs). Aims: To determine the impact of CYP2C19 metabolizer status in relation to chronic PPI therapy with a focus on the extent of esophageal inflammation, acid exposure, and motor function. Methods: This retrospective study included 54 patients with refractory GERD symptoms who underwent CYP2C19 genotyping for PPI metabolism, esophagogastroduodenoscopy, ambulatory pH study, and high-resolution esophageal manometry. Patients were divided into three groups: normal metabolizer (NM) group, intermediate metabolizer/poor metabolizer (IM/PM) group, and rapid metabolizer/ultra-rapid metabolizer (RM/UM) group. The Chi-square test was used to analyze categorical variables, and one-way ANOVA for comparing means. Results: Rapid metabolizer/ultra-rapid metabolizer (RM/UM) group more frequently had either Los Angeles grade C or D GERD (7/19, 36.8% vs 1/21, 4.8%, P = 0.011) and metaplasia of the esophagus (9/19, 47.4% vs 2/21, 9.5%, P = 0.007) when compared to the NM group. RM/UM group were more frequently offered dilatation for nonobstructive dysphagia (8/19, 42.1% vs 3/21, 14.3%, P = 0.049) and more exhibited a hypotensive lower esophageal sphincter (LES) resting pressure compared to the NM group (10/19, 52.6% vs 4/21, 19%, P = 0.026). All three groups exhibited comparable DeMeester scores when PPIs were discontinued 72 hours before the ambulatory pH study. Conclusion: CYP2C19 RMs and UMs on chronic PPI with refractory GERD symptoms exhibited greater esophageal mucosal inflammation, as observed both endoscopically and histologically, and more were found to have hypotensive LES resting pressures and more were offered esophageal dilatation.

Synthesis of (2R,4S)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.

Vaccination with a Human Papillomavirus L2 Multimer Provides Broad Protection against 17 Human Papillomavirus Types in the Mouse Cervicovaginal Challenge Model.

Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11-88) from five human alphapapillomavirus genotypes in E. coli under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil®9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard in vitro and in vivo toxicology studies suggest a promising safety profile. These findings suggest LBTA's promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).