Dual-polarization pump rejection filter in silicon nitride technology.

On-chip pump rejection filters are key building blocks in a variety of applications exploiting nonlinear phenomena, including Raman spectroscopy and photon-pair generation. Ultrahigh rejection has been achieved in the silicon technology by non-coherent cascading of modal-engineered Bragg filters. However, this concept cannot be directly applied to silicon nitride waveguides as the comparatively lower index contrast hampers the suppression of residual light propagating in the orthogonal polarization, limiting the achievable rejection. Here, we propose and demonstrate a novel, to the best of our knowledge, strategy to overcome this limitation based on non-coherent cascading of the modal- and polarization-engineered Bragg filters. Based on this concept, we experimentally demonstrate a rejection exceeding 60 dB for both polarizations, with a bandwidth of 4.4 nm. This is the largest rejection reported for silicon nitride Bragg gratings supporting both polarizations.

Short-term effect of intravitreal dexamethasone implant in refractory diabetic macular edema.

PURPOSE: To evaluate the short-term effects (hours-days) of intravitreal dexamethasone implant (IDI) in eyes with diabetic macular edema (DME) refractory to anti-vascular endothelial growth factor (VEGF) injections. METHODS: This was a prospective, single-arm, interventional clinical series. Eyes with DME and 3-9 injections of ranibizumab without a good response were included. Patients underwent a single IDI. Best-corrected visual acuity (BCVA) measurement, complete ophthalmic evaluation, and spectral-domain optical coherence tomography (SD-OCT) were performed at baseline, 2 h, 3 h, 24 h, 7 days, and 1 month. The main outcomes were change in central retinal thickness (CRT) on SD-OCT and BCVA. RESULTS: Fifteen eyes of 15 patients were included. Mean CRT decreased after treatment from 515.87 µm ± 220.00 µm at baseline to 489.60 µm ± 176.53 µm after 2 h (p = 0.126), and 450.13 µm ± 163.43 at 24 h (p = 0.006). Change in BCVA was from 0.85 ± 0.44 logMAR baseline to 0.58 ± 0.37 log MAR at 1 month (p = 0.003). CONCLUSIONS: Eyes treated with IDI showed significant decrease in CRT detectable 1 day after injection. In some patients, the effect could be observed 3 h post-implantation. TRIAL REGISTRATION: Clinicaltrials.gov NCT05736081 . Registered 20 February 2023, Retrospectively registered.

MATR3 P154S knock-in mice do not exhibit motor, muscle or neuropathologic features of ALS.

Matrin 3 is a nuclear matrix protein that has many roles in RNA processing including splicing and transport of mRNA. Many missense mutations in the Matrin 3 gene (MATR3) have been linked to familial forms of amyotrophic lateral sclerosis (ALS) and distal myopathy. However, the exact role of MATR3 mutations in ALS and myopathy pathogenesis is not understood. To demonstrate a role of MATR3 mutations in vivo, we generated a novel CRISPR/Cas9 mediated knock-in mouse model harboring the MATR3 P154S mutation expressed under the control of the endogenous promoter. The P154S variant of the MATR3 gene has been linked to familial forms of ALS. Heterozygous and homozygous MATR3 P154S knock-in mice did not develop progressive motor deficits compared to wild-type mice. In addition, ALS-like pathology did not develop in nervous or muscle tissue in either heterozygous or homozygous mice. Our results suggest that the MATR3 P154S variant is not sufficient to produce ALS-like pathology in vivo.

Effects of Etomidate on Postintubation Hypotension, Inflammatory Markers, and Mortality in Critically Ill Patients with COVID-19: An International, Multicenter, Retrospective Study.

OBJECTIVE: To evaluate the association of etomidate with postintubation hypotension, inflammation, and mortality in critically ill patients with COVID-19. DESIGN: International, multicenter, retrospective study. PARTICIPANTS: Critically ill patients hospitalized specifically for COVID-19 from three major academic institutions in the US and Europe. MAIN OUTCOME AND MEASURES: Patients were allocated into the etomidate (ET) group or another induction agent (OA) group. The primary outcome was postintubation hypotension. Secondary outcomes included postintubation inflammatory status, in-hospital mortality, and mortality at 30 days. RESULTS: 171 patients with a median age of 68 (IQR 58-73) years were included (ET, n = 98; OA, n = 73). Etomidate was associated with lower postintubation mean arterial pressure [74.33 (64-85) mm Hg versus 81.84 (69.75-94.25) mm Hg, p = 0.005] compared to other agents. No statistically significant differences were generally observed in inflammatory markers between the two groups at 7- and 14-days after admission to the intensive care unit. In-hospital mortality [77 (79%) versus 41 (56%), p = 0.003] and mortality at 30-days [78 (80%) versus 43 (59%), p = 0.006] were higher in the ET group. In multivariate logistic regression analysis, only etomidate (p = 0.009) and postintubation mean arterial pressure (p < 0.001) had a statistically significant effect on mortality, in contrast to stress-dose steroids (p = 0.301), after adjusting for creatinine (p = 0.695), blood urea nitrogen (p = 0.153), age (p = 0.055), oxygen saturation of hemoglobin (SpO2) (p = 0.941), and fraction of inspired oxygen (FiO2) (p = 0.712). CONCLUSIONS: Administration of a single-bolus dose of etomidate in critically ill patients with COVID-19 is associated with lower postintubation mean arterial pressure and higher in-hospital and 30-day mortality compared to other induction agents.

Automatic Segmentation of Facial Regions of Interest and Stress Detection Using Machine Learning.

Stress is a factor that affects many people today and is responsible for many of the causes of poor quality of life. For this reason, it is necessary to be able to determine whether a person is stressed or not. Therefore, it is necessary to develop tools that are non-invasive, innocuous, and easy to use. This paper describes a methodology for classifying stress in humans by automatically detecting facial regions of interest in thermal images using machine learning during a short Trier Social Stress Test. Five regions of interest, namely the nose, right cheek, left cheek, forehead, and chin, are automatically detected. The temperature of each of these regions is then extracted and used as input to a classifier, specifically a Support Vector Machine, which outputs three states: baseline, stressed, and relaxed. The proposal was developed and tested on thermal images of 25 participants who were subjected to a stress-inducing protocol followed by relaxation techniques. After testing the developed methodology, an accuracy of 95.4% and an error rate of 4.5% were obtained. The methodology proposed in this study allows the automatic classification of a person's stress state based on a thermal image of the face. This represents an innovative tool applicable to specialists. Furthermore, due to its robustness, it is also suitable for online applications.

Physiological stressor impact on peripheral facial temperature, Il-6 and mean arterial pressure, in young people.

Nowadays, stress is part of everyday life, whose long-term effects can trigger health risks. Among the main alterations that occur in the human body we can find the variation of inflammatory activity, blood pressure, and facial peripheral temperature. The objective of this work is to show the facial thermal behavior for men and women, as well as the differences in vascular and inflammatory responses induced by the effect of acute social stress. The Trier Social Stress Test was applied to 15 women and 15 men, free of disease, with an average age of 23.8 years and a standard deviation of 5.52. After capturing the baseline state, and at the end of the test, the inflammatory activity was measured through salivary interleukin-6; the mean blood pressure, and the capture of facial thermographic images. For the thermal images, six regions of interest (biothermomarkers) were analyzed: forehead, right cheek, left cheek, chin, nose, and corrugator muscle. The results obtained after analyzing the information were: an increase in inflammatory activity, an increase in mean blood pressure, and significant temperature changes in different areas of interest of the face, depending on gender. For men, it only appeared in the region of the nose and women's forehead, cheeks, and nose. Furthermore, the correlation between the three variables (il-6, blood pressure, and temperature) was performed and no significant values were found. Regarding the relationship between genders, only significant values were found for il-6.

FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice: CONTRIBUTIONS OF PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR (PRO-BDNF) AND MATURE BDNF.

Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age. Long term oral FTY720 in Tg mice reduced ENS aSyn aggregation and constipation, enhanced gut motility, and increased levels of brain-derived neurotrophic factor (BDNF) but produced no significant change in WT littermates. A role for BDNF was directly assessed in a cohort of young A53T mice given vehicle, FTY720, the Trk-B receptor inhibitor ANA-12, or FTY720 + ANA-12 from 1 to 4 months of age. ANA-12-treated Tg mice developed more gut aSyn aggregation as well as constipation, whereas FTY720-treated Tg mice had reduced aSyn aggregation and less constipation, occurring in part by increasing both pro-BDNF and mature BDNF levels. The data from young and old Tg mice revealed FTY720-associated neuroprotection and reduced aSyn pathology, suggesting that FTY720 may also benefit PD patients and others with synucleinopathy. Another finding was a loss of tyrosine hydroxylase immunoreactivity in gut neurons with aggregated aSyn, comparable with our prior findings in the CNS.

Assessment of a Tele-education System to Enhance Retinopathy of Prematurity Training by International Ophthalmologists-in-Training in Mexico.

PURPOSE: To evaluate a tele-education system developed to improve diagnostic competency in retinopathy of prematurity (ROP) by ophthalmologists-in-training in Mexico. DESIGN: Prospective, randomized cohort study. PARTICIPANTS: Fifty-eight ophthalmology residents and fellows from a training program in Mexico consented to participate. Twenty-nine of 58 trainees (50%) were randomized to the educational intervention (pretest, ROP tutorial, ROP educational chapters, and posttest), and 29 of 58 trainees (50%) were randomized to a control group (pretest and posttest only). METHODS: A secure web-based educational system was created using clinical cases (20 pretest, 20 posttest, and 25 training chapter-based) developed from a repository of over 2500 unique image sets of ROP. For each image set used, a reference standard ROP diagnosis was established by combining the clinical diagnosis by indirect ophthalmoscope examination and image-based diagnosis by multiple experts. Trainees were presented with image-based clinical cases of ROP during a pretest, posttest, and training chapters. MAIN OUTCOME MEASURES: The accuracy of ROP diagnosis (e.g., plus disease, zone, stage, category) was determined using sensitivity and specificity calculations from the pretest and posttest results of the educational intervention group versus control group. The unweighted kappa statistic was used to analyze the intragrader agreement for ROP diagnosis by the ophthalmologists-in-training during the pretest and posttest for both groups. RESULTS: Trainees completing the tele-education system had statistically significant improvements (P < 0.01) in the accuracy of ROP diagnosis for plus disease, zone, stage, category, and aggressive posterior ROP (AP-ROP). Compared with the control group, trainees who completed the ROP tele-education system performed better on the posttest for accurately diagnosing plus disease (67% vs. 48%; P = 0.04) and the presence of ROP (96% vs. 91%; P < 0.01). The specificity for diagnosing AP-ROP (94% vs. 78%; P < 0.01), type 2 ROP or worse (92% vs. 84%; P = 0.04), and ROP requiring treatment (89% vs. 79%; P < 0.01) was better for the trainees completing the tele-education system compared with the control group. Intragrader agreement improved for identification of plus disease, zone, stage, and category of ROP after completion of the educational intervention. CONCLUSIONS: A tele-education system for ROP education was effective in improving the diagnostic accuracy of ROP by ophthalmologists-in-training in Mexico. This system has the potential to increase competency in ROP diagnosis and management for ophthalmologists-in-training from middle-income nations.

Adult community health-promoting interventions in primary health care: A systematic review.

OBJECTIVE: To examine evidence on the effectiveness of health-promoting community interventions carried out in primary health care. METHODS: Systematic review of originals and systematic reviews of health-promoting community interventions with the participation of primary health care. A working definition of community activities was used in the inclusion criteria. Databases searched up to 2013: PUBMED, EMBASE, CINHAL, Web of SCIENCE, IBECS, IME, and PSICODOC. No restrictions on year of publication or design. Articles were reviewed by separate researchers to identify risks of bias. RESULTS: Fifty-one articles published between 1966 and 2013 were included: 11 systematic reviews and 40 originals that described 39 community interventions. There is evidence on the effectiveness of community interventions in reducing cardiovascular risk factors, encouraging physical exercise, preventing falls and improving self-care among chronic patients compared with usual individual care. The effectiveness of some interventions increases when the community is involved in their development. Most assessments show positive results despite design limitations. CONCLUSIONS: The community approach may be more effective than the individual in usual preventive interventions in primary care. There is a lack of evidence on many community interventions in primary care and further research is needed.

A model evaluation study for treatment planning of laser-induced thermal therapy.

A cross-validation analysis evaluating computer model prediction accuracy for a priori planning magnetic resonance-guided laser-induced thermal therapy (MRgLITT) procedures in treating focal diseased brain tissue is presented. Two mathematical models are considered. (1) A spectral element discretisation of the transient Pennes bioheat transfer equation is implemented to predict the laser-induced heating in perfused tissue. (2) A closed-form algorithm for predicting the steady-state heat transfer from a linear superposition of analytic point source heating functions is also considered. Prediction accuracy is retrospectively evaluated via leave-one-out cross-validation (LOOCV). Modelling predictions are quantitatively evaluated in terms of a Dice similarity coefficient (DSC) between the simulated thermal dose and thermal dose information contained within N = 22 MR thermometry datasets. During LOOCV analysis, the transient model's DSC mean and median are 0.7323 and 0.8001 respectively, with 15 of 22 DSC values exceeding the success criterion of DSC ≥ 0.7. The steady-state model's DSC mean and median are 0.6431 and 0.6770 respectively, with 10 of 22 passing. A one-sample, one-sided Wilcoxon signed-rank test indicates that the transient finite element method model achieves the prediction success criteria, DSC ≥ 0.7, at a statistically significant level.

Glucocorticoids exacerbate cognitive deficits in TDP-25 transgenic mice via a glutathione-mediated mechanism: implications for aging, stress and TDP-43 proteinopathies.

The accumulation of TDP-43 (transactive response DNA-binding protein 43) and its 25 kDa C-terminal fragment (TDP-25) is a hallmark of several neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). The majority of FTLD-TDP cases are due to loss of function mutations in the gene encoding progranulin, a secreted growth factor. In ALS, specific mutations in the gene encoding TDP-43 have been linked to the disease pathogenesis. In both cases, however, the penetrance of the mutations greatly increases during aging, suggesting that other genetic or environmental factors may facilitate the development of the disease. Using transgenic mice that overexpress the 25 kDa C-terminal fragment of TDP-43, here we show that glucocorticoids, stress hormones known to increase the brain susceptibility to neurotoxic insults, increase the levels of soluble TDP-25 and exacerbate cognitive deficits, without altering full-length TDP-43 levels. Additionally, we show that the mechanism underlying the glucocorticoid-mediated increase in TDP-25 levels is coupled to changes in the glutathione redox state. Glutathione is an antioxidant involved in protecting cells from damage caused by reactive oxygen species; notably, alterations in the ratio of reduced to oxidized glutathione, which is the primary determinant of the cellular redox state, are associated with aging and neurodegeneration. We show that restoring the ratio of reduced to oxidized glutathione blocks the glucocorticoid effects on TDP-25. These data show that glucocorticoids potentiate the neurotoxic action of TDP-25 by increasing its levels and clearly indicate the role of cellular oxidative damage in this process.

Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes in sex-dependent and sex-independent manners.

Metformin has attracted increasing interest for its potential benefits in extending healthspan and longevity. This study examined the effects of early-life metformin treatment on the development and metabolism of C57BL/6 J (B6) mice, with metformin administered to juvenile mice from 15 to 56 days of age. Metformin treatment led to decreased body weight in both sexes (P < 0.05, t-test). At 9 weeks of age, mice were euthanized and organ weights were recorded. The relative weight of retroperitoneal fat was decreased in females, while relative weights of perigonadal and retroperitoneal fat were decreased, and relative liver weight was increased in males (P < 0.05, t-test). Glucose and insulin tolerance tests (GTT and ITT) were conducted at the age of 7 weeks. ANOVA revealed a significant impairment in insulin sensitivity by the treatment, and a significantly interactive effect on glucose tolerance between sex and treatment, underscoring a disparity in GTT between sexes in response to the treatment. Metformin treatment reduced circulating insulin levels in fasting and non-fasting conditions for male mice, with no significant alterations observed in female mice. qRT-PCR analysis of glucose metabolism-related genes (Akt2, Glut2, Glut4, Irs1, Nrip1, Pi3k, Pi3kca, Pkca) in the liver and skeletal muscle reveals metformin-induced sex- and organ-specific effects on gene expression. Comparison with previous studies in heterogeneous UM-HET3 mice receiving the same treatment suggests that genetic differences may contribute to variability in the effects of metformin treatment on development and metabolism. These findings indicate that early-life metformin treatment affects development and metabolism in both sex- and genetics-dependent manners.

Senolytic Intervention Improves Cognition, Metabolism, and Adiposity in Female APP NL-F/NL-F Mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APP NL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice. Thus, four month old male and female APP NL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg Dasatinib + 50 mg/kg Quercetin, or 100 mg/kg Fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + Quercetin treatment in female APP NL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-ß (Aß) 42 and senescence associated-ß-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APP NL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

Senolytic intervention improves cognition, metabolism, and adiposity in female APPNL-F/NL-F mice.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer's disease (AD). The APPNL-F/NL-F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL-F/NL-F mice. Thus, 4-month-old male and female APPNL-F/NL-F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL-F/NL-F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-ß (Aß)42 and senescence-associated-ß-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL-F/NL-F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

Changes in Neonatal Intensive Care Unit statistics during the COVID-19 pandemic.

BACKGROUND: With the identification of COVID-19 disease in China, a pandemic began that affected health-care systems. The Neonatal Intensive Care Unit (NICU) of the Hospital de Ginecobstetricia del Centro Médico Nacional de Occidente experienced an increase in patient flow as part of the COVID-19 strategy of the Instituto Mexicano del Seguro Social (IMSS). This study aimed to analyze the impact of the COVID-19 pandemic on neonatal care and mortality indicators in our unit. METHODS: We conducted a retrospective study to compare the number of hospital births, pre-term newborns (PTNB), NICU admissions, and deaths. Changes in frequencies between 2019 and 2021 were analyzed using Poisson distribution. Changes in PTNB births, proportion of admissions, and deaths/NICU discharges were analyzed by z-test for two proportions. RESULTS: Between 2019 and 2021, the number of births increased by more than 2-fold. NICU admissions increased from 770 in 2019 to 1045 in 2021 (p < 0.01). The ratio of deaths/discharge from the service was 16.9% in 2019 and 13.1% in 2021 (p = 0.02). CONCLUSIONS: Mortality indicators in the NICU decreased from 2019 to 2021, even with the increase in the number of patients admitted during the COVID-19 pandemic.

INTRODUCCIÓN: Con la identificación de la enfermedad por COVID-19 en China, inició una pandemia que afectó a los sistemas de salud. La Unidad de Cuidados Intensivos Neonatales (UCIN) del Hospital de Ginecobstetricia del Centro Médico Nacional de Occidente del Instituto Mexicano del Seguro Social (IMSS) vio incrementado su flujo de pacientes como parte de la Estrategia COVID-19 del IMSS. El objetivo fue analizar el impacto de la pandemia COVID-19 en los indicadores de atención y mortalidad neonatal en nuestra unidad. MÉTODOS: Se realizó un estudio retrospectivo para comparar el número de nacimientos en el hospital, nacimientos de recién nacidos prematuros (RNPT), ingresos a UCIN y defunciones. Se analizaron los cambios en frecuencias entre los años 2019 a 2021 mediante la distribución de Poisson. Los cambios en nacimientos de RNPT, proporción de ingresos y defunciones/egreso en UCIN se analizaron mediante prueba Z para dos proporciones. RESULTADOS: Entre los años 2019 a 2021, el número de nacimientos incrementó más de 2 veces. Los ingresos a UCIN aumentaron de 770 en 2019, a 1045 en 2021 (p < 0.01). La proporción de defunciones/egreso del servicio fue de 16.9% en 2019, y 13.1% en 2021 (p = 0.02). CONCLUSIONES: Los indicadores de mortalidad en la UCIN disminuyeron de 2019 a 2021, aun con el incremento en el número de pacientes atendidos durante la pandemia COVID-19.

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Resistance to mild cold stress is greater in both wild-type and long-lived GHR-KO female mice.

Adapting to stress, including cold environmental temperature (eT), is crucial for the survival of mammals, especially small rodents. Long-lived mutant mice have enhanced stress resistance against oxidative and non-oxidative challenges. However, much less is known about the response of those long-lived mice to cold stress. Growth hormone receptor knockout (GHR-KO) mice are long-lived with reduced growth hormone signaling. We wanted to test whether GHR-KO mice have enhanced resistance to cold stress. To examine the response of GHR-KO mice to cold eT, GHR-KO mice were housed at mild cold eT (16 °C) immediately following weaning. Longevity results showed that female GHR-KO and wild-type (WT) mice retained similar lifespan, while both male GHR-KO and WT mice had shortened lifespan compared to the mice housed at 23 °C eT. Female GHR-KO and WT mice housed at 16 °C had upregulated fibroblast growth factor 21 (FGF21), enhanced energy metabolism, reduced plasma triglycerides, and increased mRNA expression of some xenobiotic enzymes compared to females housed at 23 °C and male GHR-KO and WT mice housed under the same condition. In contrast, male GHR-KO and WT mice housed at 16 °C showed deleterious effects in parameters which might be associated with their shortened longevity compared to male GHR-KO and WT mice housed at 23 °C. Together, this study suggests that in response to mild cold stress, sex plays a pivotal role in the regulation of longevity, and female GHR-KO and WT mice are more resistant to this challenge than the males.

How does the clinical and tomographic appearance of MRONJ influences its treatment prognosis?

OBJECTIVES: To identify clinical and tomographic prognostic factors for conservative and surgical treatment of medication-related osteonecrosis of the jaws (MRONJ). METHODS: A retrospective search identified patients treated with antiresorptive drugs (ARDs), diagnosed with Stage 1, 2 or 3 MRONJ, and having CBCT scans previous to conservative or surgical treatment. Following data collection, imaging assessment of the following parameters on each MRONJ site was performed: involvement of teeth and/or implants, presence of osteosclerosis, osteolysis, sequestrum formation, periosteal reaction, and pathological fractures. For statistical analysis, patients and lesions were divided into conservative and surgical treatment. Comparisons were made between successful and unsuccessful outcomes. Significance was set at p ≤ 0.05. RESULTS: 115 ARD-treated patients who developed 143 osteonecrosis lesions were selected. 40 patients and 58 lesions received conservative treatment, of which 14 patients (35%) and 25 lesions (43%) healed. Additionally, 75 patients and 85 lesions underwent surgery, with 48 patients (64%) and 55 lesions (65%) that healed. Clinical and tomographic risk factors for conservative treatment were MRONJ staging, tooth involvement, extensive osteosclerosis, and deep sequestrum formation (p < 0.05). Complementarily, poor prognostic indicators for surgical therapy were a short bisphosphonate (BP) holiday, MRONJ staging, absence of sequestrum formation, and presence of periosteal reaction (p < 0.05). CONCLUSIONS: Lesions at Stage 3 MRONJ, with tooth involvement, or sequestrum formation showed poor outcomes when conservative treatment is chosen. Alternatively, surgical treatment is most effective when BPs are discontinued, in Stage 1 lesions, in the presence of sequestrum formation, and absence of periosteal reaction.

Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment.

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma, tissue specific markers of senescence-associated secretory phenotype (SASP), and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D + Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q.

Prevalence of Dome-Shaped Macula and Tilted Disc Syndrome in High Myopia.

BACKGROUND AND OBJECTIVE: Dome-shaped macula (DSM) and tilted disc syndrome (TDS) are two macular abnormalities that may occur in eyes with high myopia. The aim of this study was to determine the prevalence of both entities in our population. PATIENTS AND METHODS: This was a prospective and observational study. Optical coherence tomography of the macula was performed in eyes with high myopia (spherical equivalent [SE] of -8D or greater) to assess the prevalence of DSM and TDS. RESULTS: Sixty-eight eyes were included. Three eyes (4.41%) had DSM and 8 (11.76%) eyes had TDS. The most common macular anomaly was posterior staphyloma (PS) (12 [17.65%]). From the eyes with DSM (n = 3), only two presented PS. An older age and a higher SE were predisposing factors for PS (P = 0.003). CONCLUSIONS: A lower prevalence of DSM and a higher prevalence of TDS was observed in our population compared to those reported in literature. [Ophthalmic Surg Lasers Imaging Retina 2023;54:568-572.].