Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis.

Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.

A nonequilibrium allosteric model for receptor-kinase complexes: The role of energy dissipation in chemotaxis signaling.

The Escherichia coli chemotaxis signaling pathway has served as a model system for the adaptive sensing of environmental signals by large protein complexes. The chemoreceptors control the kinase activity of CheA in response to the extracellular ligand concentration and adapt across a wide concentration range by undergoing methylation and demethylation. Methylation shifts the kinase response curve by orders of magnitude in ligand concentration while incurring a much smaller change in the ligand binding curve. Here, we show that the disproportionate shift in binding and kinase response is inconsistent with equilibrium allosteric models. To resolve this inconsistency, we present a nonequilibrium allosteric model that explicitly includes the dissipative reaction cycles driven by adenosine triphosphate (ATP) hydrolysis. The model successfully explains all existing joint measurements of ligand binding, receptor conformation, and kinase activity for both aspartate and serine receptors. Our results suggest that the receptor complex acts as an enzyme: Receptor methylation modulates the ON-state kinetics of the kinase (e.g., phosphorylation rate), while ligand binding controls the equilibrium balance between kinase ON/OFF states. Furthermore, sufficient energy dissipation is responsible for maintaining and enhancing the sensitivity range and amplitude of the kinase response. We demonstrate that the nonequilibrium allosteric model is broadly applicable to other sensor-kinase systems by successfully fitting previously unexplained data from the DosP bacterial oxygen-sensing system. Overall, this work provides a nonequilibrium physics perspective on cooperative sensing by large protein complexes and opens up research directions for understanding their microscopic mechanisms through simultaneous measurements and modeling of ligand binding and downstream responses.

Safety of the novel oral poliovirus vaccine type 2 (nOPV2) in infants and young children aged 1 to <5 years and lot-to-lot consistency of the immune response to nOPV2 in infants in The Gambia: a phase 3, double-blind, randomised controlled trial.

BACKGROUND: Novel oral poliovirus vaccine type 2 (nOPV2) has been engineered to improve the genetic stability of Sabin oral poliovirus vaccine (OPV) and reduce the emergence of circulating vaccine-derived polioviruses. This trial aimed to provide key safety and immunogenicity data required for nOPV2 licensure and WHO prequalification. METHODS: This phase 3 trial recruited infants aged 18 to <52 weeks and young children aged 1 to <5 years in The Gambia. Infants randomly assigned to receive one or two doses of one of three lots of nOPV2 or one lot of bivalent OPV (bOPV). Young children were randomised to receive two doses of nOPV2 lot 1 or bOPV. The primary immunogenicity objective was to assess lot-to-lot equivalence of the three nOPV2 lots based on one-dose type 2 poliovirus neutralising antibody seroconversion rates in infants. Equivalence was declared if the 95% CI for the three pairwise rate differences was within the -10% to 10% equivalence margin. Tolerability and safety were assessed based on the rates of solicited adverse events to 7 days, unsolicited adverse events to 28 days, and serious adverse events to 3 months post-dose. Stool poliovirus excretion was examined. The trial was registered as PACTR202010705577776 and is completed. FINDINGS: Between February and October, 2021, 2345 infants and 600 young children were vaccinated. 2272 (96·9%) were eligible for inclusion in the post-dose one per-protocol population. Seroconversion rates ranged from 48·9% to 49·2% across the three lots. The minimum lower bound of the 95% CIs for the pairwise differences in seroconversion rates between lots was -5·8%. The maximum upper bound was 5·4%. Equivalence was therefore shown. Of those seronegative at baseline, 143 (85·6%) of 167 (95% CI 79·4-90·6) infants and 54 (83·1%) of 65 (71·7-91·2) young children seroconverted over the two-dose nOPV2 schedule. The post-two-dose seroprotection rates, including participants who were both seronegative and seropositive at baseline, were 604 (92·9%) of 650 (95% CI 90·7-94·8) in infants and 276 (95·5%) of 289 (92·4-97·6) in young children. No safety concerns were identified. 7 days post-dose one, 78 (41·7%) of 187 (95% CI 34·6-49·1) infants were excreting the type 2 poliovirus. INTERPRETATION: nOPV2 was immunogenic and safe in infants and young children in The Gambia. The data support the licensure and WHO prequalification of nOPV2. FUNDING: Bill & Melinda Gates Foundation.

Mucosal immunity to poliovirus in children 0-15 years of age: A community-based study in Karachi, Pakistan in 2019.

This study assesses poliovirus type 1 (PV1) immunity in children to inform the contribution of mucosal immunity in and preventing poliovirus circulation. A community-based study was conducted in peri-urban Karachi, Pakistan. Randomly selected children (0-15 years) received oral poliovirus vaccine (OPV) challenge dose. Blood and stool samples were collected at several time points and evaluated for polio-neutralizing antibodies and serotype-specific poliovirus, respectively. 81/589 (14%) children excreted PV1 7 days post-OPV-challenge; 70/81 (86%) were seropositive at baseline. 12/610 (2%) were asymptomatic Wild Poliovirus Type 1 (WPV1) excretors. Most poliovirus excretors had humoral immunity, suggesting mucosal immunity in these children likely waned or never developed. Without mucosal immunity, they are susceptible to poliovirus infection, shedding, and transmission. Asymptomatic WPV1 excretion suggests undetected poliovirus circulation within the community.

Two-Year Duration of Immunity of Inactivated Poliovirus Vaccine: A Follow-up Study in Pakistan in 2020.

This was a follow-up study conducted in 2020 assessing changes in levels of type 2 poliovirus-neutralizing antibodies 2 years postimmunization in children who received inactivated poliovirus vaccine (IPV) in Karachi, Pakistan. Unexpectedly, the findings revealed an increase in seroprevalence of type 2 antibodies from 73.1% to 81.6% 1 year and 2 years after IPV, respectively. The increase in type 2 immunity could result from the intensive transmission of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Karachi during the second year of IPV administration. This study suggests that the cVDPV2 outbreak detected in Pakistan infected large proportions of children in Karachi. Clinical Trials Registration . NCT03286803.

Evaluation of the safety, immunogenicity, and faecal shedding of novel oral polio vaccine type 2 in healthy newborn infants in Bangladesh: a randomised, controlled, phase 2 clinical trial.

BACKGROUND: Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants. METHODS: In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0-3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on ClinicalTrials.gov, NCT04693286. FINDINGS: Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 [67%]) or placebo (n=110 [33%]). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies. INTERPRETATION: nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies. FUNDING: Bill & Melinda Gates Foundation.

Organocatalytic Synthesis and DNA Interactive Studies of New 1,2,3-triazolyl-thiazolidines Hybrids.

An organocatalytic [3+2] cycloaddition reaction between thiazolidine-containing ß-ketoester 1 and aryl azides 2 was employed to synthesize new 1,2,3-triazolyl-thiazolidine hybrids 3. In this metal-free approach, twelve compounds were isolated in yields ranging from 23 % to 96 % by using diethylamine (10 mol%) and DMSO at 75 °C for 24 hours. DNA-binding assays were conducted through absorption, emission spectroscopy and viscosimetry analysis, to evaluate the interaction capacity of the studied derivatives with nucleic acids. All the synthesized compounds were evaluated for their interactions with a specific group of compounds containing the pharmacophoric groups triazole and thiazolidine through a molecular docking speculative study, aimed at identifying the interaction profile of these compounds with DNA. The obtained results suggest that 1,2,3-triazolyl-thiazolidine hybrids could be a promising approach in the development of novel therapeutic agents targeting DNA-related processes.

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.

Remission and low disease activity are associated with lower healthcare costs: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort. METHODS: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions. RESULTS: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states. CONCLUSIONS: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.

Reovirus infection is regulated by NPC1 and endosomal cholesterol homeostasis.

Cholesterol homeostasis is required for the replication of many viruses, including Ebola virus, hepatitis C virus, and human immunodeficiency virus-1. Niemann-Pick C1 (NPC1) is an endosomal-lysosomal membrane protein involved in cholesterol trafficking from late endosomes and lysosomes to the endoplasmic reticulum. We identified NPC1 in CRISPR and RNA interference screens as a putative host factor for infection by mammalian orthoreovirus (reovirus). Following internalization via clathrin-mediated endocytosis, the reovirus outer capsid is proteolytically removed, the endosomal membrane is disrupted, and the viral core is released into the cytoplasm where viral transcription, genome replication, and assembly take place. We found that reovirus infection is significantly impaired in cells lacking NPC1, but infection is restored by treatment of cells with hydroxypropyl-ß-cyclodextrin, which binds and solubilizes cholesterol. Absence of NPC1 did not dampen infection by infectious subvirion particles, which are reovirus disassembly intermediates that bypass the endocytic pathway for infection of target cells. NPC1 is not required for reovirus attachment to the plasma membrane, internalization into cells, or uncoating within endosomes. Instead, NPC1 is required for delivery of transcriptionally active reovirus core particles from endosomes into the cytoplasm. These findings suggest that cholesterol homeostasis, ensured by NPC1 transport activity, is required for reovirus penetration into the cytoplasm, pointing to a new function for NPC1 and cholesterol homeostasis in viral infection.

Differences in Glycemic Control for Inpatients with Type 1 Diabetes on Insulin Pump Versus Subcutaneous Insulin Therapy.

BACKGROUND: Inpatient use of insulin pump therapy has been increasing due to greater availability of this technology, however there is a paucity of research that investigates glycemic control of inpatient insulin pump users. OBJECTIVE: To compare the glycemic control of hospitalized patients with type 1 diabetes (T1D) who used insulin pump vs. multiple daily injections (MDI). DESIGN: Retrospective chart review. PARTICIPANTS: Patients with T1D who were hospitalized between January 1, 2017, and December 31, 2019, in an academic medical center in the New York metropolitan area. MAIN MEASURES: Patients were categorized into three groups based on their method of insulin administration: "pump only" group used insulin pump exclusively, "MDI only" group used MDI only, and "intermittent pump" group used a combination of both methods. The primary endpoints are mean blood glucose, rates of hypoglycemic events (blood glucose < 70 mg/dL), and rates of hyperglycemic events (blood glucose > 250 mg/dL). Separate multivariable Poisson regressions were performed to determine the association between the type of insulin administration and rate outcomes (i.e., rate of hypoglycemic events and rate of hyperglycemic events). RESULTS: The study included 78 patients with a mean age of 51, who were mostly male (54%), and white (72%). The average proportion of glucose measurements that were hyperglycemic for the "pump only", "MDI only", and "intermittent pump" groups were 0.11 (SD = 0.11), 0.25 (SD = 0.19), and 0.24 (SD = 0.25), respectively. The "pump only" group has a significantly lower proportion of hyperglycemic events as compared to the "MDI only" group (p = 0.0227). CONCLUSIONS: In this sample, patients who exclusively used their insulin pump while inpatient had a lower rate of hyperglycemic events than patients who used MDI only; suggesting that select patients can safely continue their insulin pump therapy in the inpatient setting.

Time to diagnosis in systemic lupus erythematosus: Associated factors and its impact on damage accrual and mortality. Data from a multi-ethnic, multinational Latin American lupus cohort.

BACKGROUND: Systemic lupus erythematosus (SLE) often mimics symptoms of other diseases, and the interval between symptom onset and diagnosis may be long in some of these patients. Aims: To describe the characteristics associated with the time to SLE diagnosis and its impact on damage accrual and mortality in patients with SLE from a Latin American inception cohort. METHODS: Patients were from a multi-ethnic, multi-national Latin-American SLE inception cohort. All participating centers had specialized lupus clinics. Socio-demographic, clinical/laboratory, disease activity, damage, and mortality between those with a longer and a shorter time to diagnosis were compared using descriptive statistical tests. Multivariable Cox regression models with damage accrual and mortality as the end points were performed, adjusting for age at SLE diagnosis, gender, ethnicity, level of education, and highest dose of prednisone for damage accrual, plus highest dose of prednisone, baseline SLEDAI, and baseline SDI for mortality. RESULTS: Of the 1437 included in these analyses, the median time to diagnosis was 6.0 months (Q1-Q3 2.4-16.2); in 721 (50.2%) the time to diagnosis was longer than 6 months. Patients whose diagnosis took longer than 6 months were more frequently female, older at diagnosis, of Mestizo ethnicity, not having medical insurance, and having "non-classic" SLE symptoms. Longer time to diagnosis had no impact on either damage accrual (HR 1.09, 95% CI 0.93-1.28, p = 0.300) or mortality (HR 1.37, 95% CI 0.88-2.12, p = 0.200). CONCLUSIONS: In this inception cohort, a maximum time of 24 months with a median of 6 months to SLE diagnosis had no apparent negative impact on disease outcomes (damage accrual and mortality).

Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Structural Relationships between Asthma and Dental Caries in Children: A Birth Cohort Study in Southern Brazil.

INTRODUCTION: There is an inconclusive causal association between asthma symptoms and dental caries in the primary dentition. This study aimed to investigate, using SEM (structural equation modeling), a possible causal relation between asthma and dental caries in the primary dentition. METHODS: Using data from the 2004 Pelotas Birth Cohort Study, a sub-sample of 1,303 individuals was selected. Dental caries was clinically evaluated at 5 years old based on decayed, missing, and filled tooth (dmft) index criteria. Asthma-related symptoms (wheezing and shortness of breath) at 1- and 4-year-olds composed a latent variable and were the main exposures to caries occurrence. SEM was used to identify possible direct, indirect, and mediated effects of asthma in primary dentition dental caries. RESULTS: The general prevalence of caries at age 5 was 1.95 (SD: 3.56). When comparing the dmft values for children with asthma symptoms and those without, they presented similar values in both periods where asthma symptoms were evaluated (1- and 4-year-old). SEM analysis showed that asthma was neither directly nor indirectly related to dental caries. CONCLUSION: Asthma, using a latent variable constructed based on asthma symptoms, showed no causal effect on dental caries occurrence in the primary dentition.

Everything old is new again. revisiting hypophysectomy for the treatment of refractory cancer-related pain: a systematic review.

Cancer-related pain is a common and debilitating condition that can significantly affect the quality of life of patients. Opioids, NSAIDs, and antidepressants are among the first-line therapies, but their efficacy is limited or their use can be restricted due to serious side effects. Neuromodulation and lesioning techniques have also proven to be a valuable instrument for managing refractory pain. For patients who have exhausted all standard treatment options, hypophysectomy may be an effective alternative treatment. We conducted a comprehensive systematic review of the available literature on PubMed and Scielo databases on using hypophysectomy to treat refractory cancer-related pain. Data extraction from included studies included study design, treatment model, number of treated patients, sex, age, Karnofsky Performance Status (KPS) score, primary cancer site, lead time from diagnosis to treatment, alcohol injection volume, treatment data, and clinical outcomes. Statistical analysis was reported using counts (N, %) and means (range). The study included data from 735 patients from 24 papers treated with hypophysectomy for refractory cancer-related pain. 329 cancer-related pain patients were treated with NALP, 216 with TSS, 66 with RF, 55 with Y90 brachytherapy, 51 with Gamma Knife radiosurgery (GK), and 18 with cryoablation. The median age was 58.5 years. The average follow-up time was 8.97 months. Good pain relief was observed in 557 out of 735 patients, with complete pain relief in 108 out of 268 patients. Pain improvement onset was observed 24 h after TSS, a few days after NALP or cryoablation, and a few days to 4 weeks after GK. Complications varied among treatment modalities, with diabetes insipidus (DI) being the most common complication. Although mostly forgotten in modern neurosurgical practice, hypophysectomy is an attractive option for treating refractory cancer-related pain after failure of traditional therapies. Radiosurgery is a promising treatment modality due to its high success rate and reduced risk of complications.

Demographic Variables Associated With Diabetes Technology Awareness or Use in Adults With Type 2 Diabetes.

Background: Studies in populations with type 1 diabetes highlight racial/ethnic disparities in the use of diabetes technology; however, little is known about disparities among those with type 2 diabetes. This project investigates the racial/ethnic and socioeconomic disparities in diabetes technology awareness and use in adults with type 2 diabetes in the ambulatory setting. Methods: Adults ≥40 years of age with type 2 diabetes in ambulatory care were invited to participate via an e-mail link to a de-identified REDCap (Research Electronic Data Capture) questionnaire. Variables, including awareness and use of continuous glucose monitoring (CGM) and insulin pumps, were summarized descriptively using frequencies and percentages and were compared across racial/ethnic groups, education level, and income using Pearson χ2 or Fisher exact tests. Results: The study included 116 participants, most of whom (62%) were White, elderly Medicare recipients. Compared with White participants, those of racially/ethnically minoritized groups were less likely to be aware of CGM (P = 0.013) or insulin pumps (P = 0.001). Participants with a high school education or less were also less likely to be aware of insulin pumps (P = 0.041). Interestingly, neither awareness nor use of CGM or insulin pumps was found to be associated with income. Conclusion: This cross-sectional analysis suggests that racially/ethnically minoritized groups and individuals with lower education have less awareness of CGM or insulin pumps.

Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

Uncovering genetic causes of hypophosphatemia.

BACKGROUND: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. METHODS: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17-55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ≤2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). RESULTS: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. CONCLUSION: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.

Mammalian Orthoreovirus Reassortment Proceeds with Little Constraint on Segment Mixing.

Segmentation of viral genomes provides the potential for genetic exchange within coinfected cells. However, for this potential to be realized, coinfecting genomes must mix during the viral life cycle. The efficiency of reassortment, in turn, dictates its potential to drive evolution. The opportunity for mixing within coinfected cells may vary greatly across virus families, such that the evolutionary implications of genome segmentation differ as a result of core features of the viral life cycle. To investigate the relationship between viral replication compartments and genetic exchange, we quantified reassortment in mammalian orthoreovirus (reovirus). Reoviruses carry a 10-segmented, double-stranded RNA genome, which is replicated within proteinaceous structures termed inclusion bodies. We hypothesized that inclusions impose a barrier to reassortment. We quantified reassortment between wild-type (wt) and variant (var) reoviruses that differ by one nucleotide per segment. Studies of wt/var systems in both T1L and T3D backgrounds revealed frequent reassortment without bias toward particular genotypes. However, reassortment was more efficient in the T3D serotype. Since T1L and T3D viruses exhibit different inclusion body morphologies, we tested the impact of this phenotype on reassortment. In both serotypes, reassortment levels did not differ by inclusion morphology. Reasoning that the merging of viral inclusions may be critical for genome mixing, we then tested the effect of blocking merging. Reassortment proceeded efficiently even under these conditions. Our findings indicate that reovirus reassortment is highly efficient despite the localization of many viral processes to inclusion bodies, and that the robustness of this genetic exchange is independent of inclusion body structure and fusion. IMPORTANCE Quantification of reassortment in diverse viral systems is critical to elucidate the implications of genome segmentation for viral evolution. In principle, genome segmentation offers a facile means of genetic exchange between coinfecting viruses. In practice, there may be physical barriers within the cell that limit the mixing of viral genomes. Here, we tested the hypothesis that localization of the various stages of the mammalian orthoreovirus life cycle within cytoplasmic inclusion bodies compartmentalizes viral replication and limits genetic exchange. Contrary to this hypothesis, our data indicate that reovirus reassortment occurs readily within coinfected cells and is not strongly affected by the structure or dynamics of viral inclusion bodies. We conclude that the potential for reassortment to contribute to reovirus evolution is high.

Electrophile-Promoted Nucleophilic Cyclization of 2-Alkynylindoles to Give 4-Substituted Oxazinoindolones.

A method for the synthesis of 4-organoselanyl oxazinoindolone derivatives by the cascade cyclization of N-(alkoxycarbonyl)-2-alkynylindoles using iron(III) chloride and diorganyl diselenides as promoters was developed. This protocol was applied to a series of N-(alkoxycarbonyl)-2-alkynylindoles containing different substituents. The reaction conditions also tolerated a variety of diorganyl diselenides having both electron donating and electron withdrawing groups. However, the reaction did not work for diorganyl disulfides and ditellurides. The reaction mechanism seems to proceed via an ionic pathway and the cooperative action between iron(III) chloride and diorganyl diselenides is crucial for successful cyclization. We also found that using the same starting materials, by simply changing the electrophilic source to iodine, led to the formation of 4-iodo-oxazinoindolones. The high reactivity of Csp2 -Se and Csp2 -I bonds were tested under cross-coupling conditions leading to the preparation of a new class of functionalized indole derivatives. In addition, the absorption, emission and electrochemical properties of 4-organoselanyl oxazinoindolones showed an important relationship with the substituents of the aromatic rings. The advantages of the methodology include the use of electrophilic to promote the cyclization reaction and functionalization of the indole ring, and the electronic properties presented by the prepared compounds can be exploited as probes, analyte detectors and optical materials.