Long-term predominance in childhood colonization of the multidrug-resistant lineage 6C/ST386 of Streptococcus pneumoniae after universal immunization with the 10-valent pneumococcal conjugate vaccine in Brazil.

BACKGROUND: A study conducted in the city of Niterói/RJ, four years after the introduction of the pneumococcal conjugate vaccine in Brazil, reported the emergence of non-vaccine serotype 6C Streptococcus pneumoniae associated with carriage in children. The multidrug-resistant (MDR) lineage ST386 was predominant among 6C isolates. A subsequent study, in 2019, reported the continued prevalence of 6C as the main serotype. This study aims to determine the genetic lineages of serotype 6C S. pneumoniae obtained from the 2019 study and evaluate the status of ST386 in this population. METHODS: Serotype 6C S. pneumoniae isolates were obtained during the 2019 study. Lineages were determined by MLST and changes in ST386 status between 2014 and 2019 were verified by a two-tailed Fisher's exact test. RESULTS: Of the 16 serotype 6C isolates recovered during 2019, 10 (62.5 %) belonged to ST386, remaining predominant in the population. The second most frequent was ST2777 represented by four (25 %) isolates. Both ST63 and ST3280 only had one (6.25 %) isolate each. Comparison of ST386 proportion between 2014 and 2019 showed no significant changes within the population. CONCLUSIONS: This study was able to confirm the stability on the occurrence of the MDR lineage ST386 in children in our setting nine years after the introduction of PCV10 in Brazil.

Effect of age-related premium readjustment on health insurance cancellation in Brazil: Regression discontinuity approach.

Age is one of the most relevant observable risk attributes in determining the value of health insurance premiums. Empirical evidence indicates that the cost of health insurance is the leading cause of contract switching, which can compromise access to healthcare services and potentially result in treatment discontinuities. Using data from a Health Maintenance Organization in the Southern region of Brazil, we examined the effect of health plan price readjustment resulting from changes in the beneficiary's age group on disenrollment or switches to a more limited coverage plan. The estimates were obtained using the method of regression discontinuity. The main findings indicate that for age group transitions at 59 years old, the price readjustment effect led to an increase in contract cancellations and switching to cheaper plans. These findings highlight that an important consequence of the difference in premium sensitivity among age groups is that the exit of individuals from the health insurance sector is selective in age. The results of this paper can support policymaking to improve access to health insurance.

Impact of increased pre-start diet density on broiler chick behavior, corticosterone levels, and performance responses under cold stress during early life.

This study assessed the effects of increased pre-start diet density on the metabolism, crop filling, and overall performance of broilers under cold stress during their initial 14 days of life. Using 576 one-day-old Cobb500 male chicks from 27-week-old breeders, the experiment employed a 2 × 2 arrangement, varying thermal conditions (thermoneutrality or cold stress at 18 °C for 8 h) and pre-start diet composition (21.5% crude protein, 2970 kcal/kg or 22.5%, 3050 kcal/kg). The cold stress group exhibited lower cloacal temperature and decreased crop filling rate during the first two days (P < 0.05). Chick behavior was significantly affected at 1 and 5 days (P < 0.05), and corticosterone levels in serum were higher for the cold stress group at 7 days (P < 0.05). Feed intake at 7 days was lower in the high-density feed group (P < 0.05). No significant interactions were observed for feed intake, body weight gain, or feed conversion ratio at 7 and 35 days (P > 0.05). Cold stress resulted in performance losses, impacting feed conversion and the Productive Efficiency Index. The dense diet influenced performance only within the first week, with subsequent diets showing no effect, suggesting dietary manipulation alone was insufficient to mitigate cold stress-induced losses.

Synthetic Process Development of (R)-(+)-1,2-Epoxy-5-hexene: An Important Chiral Building Block.

Herein, we describe two practical approaches to synthesize (R)-(+)-1,2-epoxy-5-hexene from inexpensive and readily available raw materials and reagents. The first approach is a two-step sequence, involving an epoxidation with meta-chloroperoxybenzoic acid (mCPBA) and a chiral resolution with (salen)Co(II), producing (R)-(+)-1,2-epoxy-5-hexene in 24-30% overall yield. The second approach utilizes readily available (R)-epichlorohydrin as the starting material and features an epoxide ring-opening reaction with allylMgCl and the NaOH-mediated ring closure reaction. Development of this two-step process affords R-(+)-1,2-epoxy-5-hexene in overall isolated yields of 55-60% with an exceptional purity profile. Both approaches have been successfully demonstrated on 100-200 g scales.

Emerging Contributions of Pluripotent Stem Cells to Reproductive Technologies in Veterinary Medicine.

The generation of mature gametes and competent embryos in vitro from pluripotent stem cells has been successfully achieved in a few species, mainly in mice, with recent advances in humans and scarce preliminary reports in other domestic species. These biotechnologies are very attractive as they facilitate the understanding of developmental mechanisms and stages that are generally inaccessible during early embryogenesis, thus enabling advanced reproductive technologies and contributing to the generation of animals of high genetic merit in a short period. Studies on the production of in vitro embryos in pigs and cattle are currently used as study models for humans since they present more similar characteristics when compared to rodents in both the initial embryo development and adult life. This review discusses the most relevant biotechnologies used in veterinary medicine, focusing on the generation of germ-cell-like cells in vitro through the acquisition of totipotent status and the production of embryos in vitro from pluripotent stem cells, thus highlighting the main uses of pluripotent stem cells in livestock species and reproductive medicine.

Correlations between ambient air pollution and the prevalence of hospitalisations and emergency room visits for respiratory diseases in children: a systematic review.

OBJECTIVE: It is known that exposure to air pollution is associated with an increased risk for cardiovascular and respiratory diseases. This review aimed to summarise observational studies on the impact of short and long-term exposure to ambient air pollution on prevalence of hospitalisations and/or emergency department visits caused by respiratory diseases in children and adolescents. SOURCES: Pubmed, Scopus, Embase and Cochrane Library databases were searched for the years 2018 to December 2022, including studies in any language. SUMMARY OF THE FINDINGS: A total of 15 studies published between 2018 and 15 January 2022 were included in this review. PM2.5 was the most type of particulate matter studied. Short-term exposure to PM2,5, PM10, NO2, SO2 and O3, even at concentrations less than the current health-based guidelines, was significantly correlated with increased risk of outpatient/hospital visits and hospitalisations for respiratory diseases by children. CONCLUSIONS: Our findings emphasise the importance and urgency of long-term control of air pollution and pollution-related diseases, especially among children and adolescents. There is a need for further research employing more homogeneous methodologies for assessing exposure and outcome measurements, in order to enable systematic reviews with meta-analysis.

Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Could poor glycaemic control be a predictor of walking speed decline in older adults? Evidence from the English Longitudinal Study of Ageing.

AIM: Although diabetes is a risk factor for walking speed decline in older adults, it remains unclear how glycaemic control [assessed by glycated haemoglobin (HbA1c)] might affect the long-term trajectories of walking speed. We investigated whether the glycaemic control status accelerates the walking speed decline and whether this decline differs depending on previous mobility conditions. MATERIALS AND METHODS: In total, 3202 individuals aged ≥60 years from the English Longitudinal Study of Ageing (ELSA) were classified at baseline and after 4 and 8 years of follow-up according to glycaemic control status as 'without diabetes' (no self-reported diabetes and HbA1c <6.5%), 'good glycaemic control' (self-reported diabetes and HbA1c ≥6.5% and <7.0%) and 'poor glycaemic control' (PGC) (self-reported diabetes and HbA1c ≥7.0%). The generalized linear mixed models verified the walking speed trajectories in m/s. A second analysis was performed, including only participants without slowness at baseline (>0.8 m/s). RESULTS: Compared with the status 'without diabetes', the annual walking speed decline was -0.015 m/s for PGC and -0.011 m/s for good glycaemic control, totalling -0.160 and -0.130 m/s, respectively, over 8 years. Among those without slowness at baseline, only PGC had a significant walking speed decline, corresponding to -0.014 m/s per year and -0.222 m/s over 8 years. CONCLUSIONS: Poor glycaemic control is a discriminator of walking speed decline in older adults, regardless of previous mobility conditions. It may serve as an early screening tool for those at risk of decreased functional performance later in life.

The Burden of Chagas Disease in the Contemporary World: The RAISE Study.

Chagas disease (ChD), a Neglected Tropical Disease, has witnessed a transformative epidemiological landscape characterized by a trend of reduction in prevalence, shifting modes of transmission, urbanization, and globalization. Historically a vector-borne disease in rural areas of Latin America, effective control measures have reduced the incidence in many countries, leading to a demographic shift where most affected individuals are now adults. However, challenges persist in regions like the Gran Chaco, and emerging oral transmission in the Amazon basin adds complexity. Urbanization and migration from rural to urban areas and to non-endemic countries, especially in Europe and the US, have redefined the disease's reach. These changing patterns contribute to uncertainties in estimating ChD prevalence, exacerbated by the lack of recent data, scarcity of surveys, and reliance on outdated models. Besides, ChD's lifelong natural history, marked by acute and chronic phases, introduces complexities in diagnosis, particularly in non-endemic regions where healthcare provider awareness is low. The temporal dissociation of infection and clinical manifestations, coupled with underreporting, has rendered ChD invisible in health statistics. Deaths attributed to ChD cardiomyopathy often go unrecognized, camouflaged under alternative causes. Understanding these challenges, the RAISE project aims to reassess the burden of ChD and ChD cardiomyopathy. The project is a collaborative effort of the World Heart Federation, Novartis Global Health, the University of Washington's Institute for Health Metrics and Evaluation, and a team of specialists coordinated by Brazil's Federal University of Minas Gerais. Employing a multidimensional strategy, the project seeks to refine estimates of ChD-related deaths, conduct systematic reviews on seroprevalence and prevalence of clinical forms, enhance existing modeling frameworks, and calculate the global economic burden, considering healthcare expenditures and service access. The RAISE project aspires to bridge knowledge gaps, raise awareness, and inform evidence-based health policies and research initiatives, positioning ChD prominently on the global health agenda.

The economic burden of Chagas disease: A systematic review.

BACKGROUND: Chagas disease (CD) is a neglected disease affecting millions worldwide, yet little is known about its economic burden. This systematic review is part of RAISE project, a broader study that aims to estimate the global prevalence, mortality, and health and economic burden attributable to chronic CD and Chronic Chagas cardiomyopathy. The objective of this study was to assess the main costs associated with the treatment of CD in both endemic and non-endemic countries. METHODS: An electronic search of the Medline, Lilacs, and Embase databases was conducted until 31st, 2022, to identify and select economic studies that evaluated treatment costs of CD. No restrictions on place or language were made. Complete or partial economic analyses were included. RESULTS: Fifteen studies were included, with two-thirds referring to endemic countries. The most commonly investigated cost components were inpatient care, exams, surgeries, consultation, drugs, and pacemakers. However, significant heterogeneity in the estimation methods and presentation of data was observed, highlighting the absence of standardization in the measurement methods and cost components. The most common component analyzed using the same metric was hospitalization. The mean annual hospital cost per patient ranges from $25.47 purchasing power parity US dollars (PPP-USD) to $18,823.74 PPP-USD, and the median value was $324.44 PPP-USD. The lifetime hospital cost per patient varies from $209,44 PPP-USD for general care to $14,351.68 PPP-USD for patients with heart failure. DISCUSSION: Despite the limitations of the included studies, this study is the first systematic review of the costs of CD treatment. The findings underscore the importance of standardizing the measurement methods and cost components for estimating the economic burden of CD and improving the comparability of cost components magnitude and cost composition analysis. Finally, assessing the economic burden is essential for public policies designed to eliminate CD, given the continued neglect of this disease.

HSP60 mimetic peptides from Mycobacterium leprae as new antigens for immunodiagnosis of Leprosy.

The early diagnosis of leprosy serves as an important tool to reduce the incidence of this disease in the world. Phage display (PD) technology can be used for mapping new antigens to the development of immunodiagnostic platforms. Our objective was to identify peptides that mimic Mycobacterium leprae proteins as serological markers using phage display technology. The phages were obtained in the biopanning using negative and positive serum from household contacts and leprosy patients, respectively. Then, the peptides were synthesized and validated in silico and in vitro for detection of IgG from patients and contacts. To characterize the native protein of M. leprae, scFv antibodies were selected against the synthetic peptides by PD. The scFv binding protein was obtained by immunocapture and confirmed using mass spectrometry. We selected two phase-fused peptides, MPML12 and MPML14, which mimic the HSP60 protein from M. leprae. The peptides MPML12 and MPML14 obtained 100% and 92.85% positivity in lepromatous patients. MPML12 and MPM14 detect IgG, especially in the multibacillary forms. The MPML12 and MPML14 peptides had positivity of 11.1% and 16.6% in household contacts, respectively. There was no cross-reaction in patient's samples with visceral leishmaniasis, tuberculosis and other mycobacteriosis for both peptides. Given these results and the easy obtainment of mimetic antigens, our peptides are promising markers for application in the diagnosis of leprosy, especially in endemic and hyperendemic regions.

Porcine Germ Cells Phenotype during Embryonic and Adult Development.

Primordial germ cells (PGCs) are the precursors of gametes. Due to their importance for the formation and reproduction of an organism, understanding the mechanisms and pathways of PGCs and the differences between males and females is essential. However, there is little research in domestic animals, e.g., swine, regarding the epigenetic and pluripotency profiles of PGCs during development. This study analyzed the expression of epigenetic and various pluripotent and germline markers associated with the development and differentiation of PGCs in porcine (pPGCs), aiming to understand the different gene expression profiles between the genders. The analysis of gonads at different gestational periods (from 24 to 35 days post fertilization (dpf) and in adults) was evaluated by immunofluorescence and RT-qPCR and showed phenotypic differences between the gonads of male and female embryos. In addition, the pPGCs were positive for OCT4 and VASA; some cells were H3k27me3 positive in male embryos and adult testes. In adults, the cells of the testes were positive for germline markers, as confirmed by gene expression analysis. The results may contribute to understanding the pPGC pathways during reproductive development, while also contributing to the knowledge needed to generate mature gametes in vitro.

Is dynapenic abdominal obesity a risk factor for cardiovascular mortality? A competing risk analysis.

BACKGROUND: Dynapenic abdominal obesity has been shown as a risk factor for all-cause mortality in older adults. However, there is no evidence on the association between this condition and cardiovascular mortality. OBJECTIVE: We aimed to investigate whether dynapenic abdominal obesity is associated with cardiovascular mortality in individuals aged 50 and older. METHODS: A longitudinal study with an 8-year follow-up was conducted involving 7,030 participants of the English Longitudinal Study of Ageing study. Abdominal obesity and dynapenia were respectively defined based on waist circumference (> 102 cm for men and > 88 cm for women) and grip strength (< 26 kg for men and < 16 kg for women). The sample was divided into four groups: non-dynapenic/non-abdominal obesity (ND/NAO), non-dynapenic/abdominal obesity (ND/AO), dynapenic/non-abdominal obesity (D/NAO) and dynapenic/abdominal obesity (D/AO). The outcome was cardiovascular mortality. The Fine-Grey regression model was used to estimate the risk of cardiovascular mortality as a function of abdominal obesity and dynapenia status in the presence of competing events controlled by socio-demographic, behavioural and clinical variables. RESULTS: The risk of cardiovascular mortality was significantly higher in individuals with D/AO compared with ND/NAO (SHR 1.85; 95% CI: 1.15-2.97). D/NAO was also associated with cardiovascular mortality (SHR: 1.62; 95% CI: 1.08-2.44). CONCLUSION: Dynapenic abdominal obesity is associated with cardiovascular mortality, with a larger effect size compared to dynapenia alone in individuals older than 50 years. Thus, prevention strategies and clinical interventions that enable mitigating the harmful effects of these conditions should be adopted to diminish such risk.

Highly water-soluble dapsone nanocrystals: Towards innovative preparations for an undermined drug.

Dapsone (DAP)is a dual-function drug substance; however, its limited water solubility may impair its bioavailability. Drug nanocrystals are an alternative to overcome this limitation. Herein, a DAP nanosuspension was prepared using adesign space approach aiming to investigate the influence of raw material properties and process parameters on the critical quality attributes of the drugnanocrystals. Optimized nanocrystals with 206.3 ± 6.7 nm using povacoat™ as stabilizer were made. The nanoparticles were characterized by dynamic light scattering, laser diffraction, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and saturation solubility. Compared to the raw material, the nanocrystals were 250-times smaller. Meanwhile, its crystalline state remained basically unchanged even after milling and drying. The nanosuspension successfully maintained its physical stability inlong-termandaccelerated stability studiesover, 4 and 3 months. Furthermore, toxicity studiesshowed low a toxicity at a20 mg/kg. As expected for nanocrystals, the size reduction improvedsaturation solubility3.78 times in water. An attempt to scale up from lab to pilot scale resulted nanocrystals of potential commercial quality. In conclusion, the present study describes the development of dapsone nanocrystals for treating infectious and inflammatory diseases. The nanocrystal formuation can be scaled up for commercial use.

Does the incidence of frailty differ between men and women over time?

BACKGROUND/OBJECTIVE: The mechanisms, risk factors and influence of sex on the incidence of frailty components are not fully understood. The aim of this study was to analyse sex differences in factors associated with the increase in the number of frailty components. METHODS: A 12-year follow-up analysis was conducted with 1,747 participants aged ≥ 60 of the ELSA Study with no frailty at baseline. Generalised linear mixed models were used to analyse the increase in the number of frailty components stratified by sex, considering socioeconomic, behavioural, clinical and biochemical characteristics as exposure variables. RESULTS: The increase in the number of frailty components in both sexes was associated with an advanced age (70 to 79 years and 80 years or older), low educational level, sedentary lifestyle, elevated depressive symptoms, joint disease, high C-reactive protein levels, perception of poor vision and uncontrolled diabetes (p < 0.05). Osteoporosis, low weight, heart disease, living with one or more people and perception of poor hearing were associated with an increase in the number of frailty components in men. High fibrinogen concentration, controlled diabetes, stroke and perception of fair vision were associated with the outcome in women (p < 0.05). Obese women and men and overweight women had a lower increase in the number of frailty components compared to those in the ideal weight range. CONCLUSIONS: Socioeconomic factors, musculoskeletal disorders, heart disease and low weight seem to sustain the frailty process in men, whereas cardiovascular and neuroendocrine disorders seem to sustain the frailty process in women.

Erythema elevatum diutinum in a patient with rheumatoid arthritis.

Erythema elevatum diutinum (EED) is a rare cutaneous neutrophilic vasculitis with many associated diseases reported in the literature. We report a 65-year-old woman with painful and itchy lesions on her elbows, hands, knees, and foot for a year. Histopathologic examination confirmed the diagnosis of erythema elevatum diutinum and treatment with dapsone produced significant clinical improvement within few weeks. Erythema elevatum diutinum is a rare disease that should be considered in patients with violaceous nodular plaques located over the extensor regions of the limbs. Knowledge of this unusual pathology and its association helps to avoid misdiagnosis and late treatment.

Potential of [11C](R)-PK11195 PET Imaging for Evaluating Tumor Inflammation: A Murine Mammary Tumor Model.

BACKGROUND: Breast tumor inflammation is an immunological process that occurs mainly by mediation of Tumor-Associated Macrophages (TAM). Aiming for a specific measurement of tumor inflammation, the current study evaluated the potential of Positron Emission Tomography (PET) imaging with [11C](R)-PK11195 to evaluate tumor inflammation in a mammary tumor animal model. METHODS: Female Balb/C mice were inoculated with 4T1 cells. The PET imaging with [11C](R)-PK11195 and [18F]FDG was acquired 3 days, 1 week, and 2 weeks after cell inoculation. RESULTS: The [11C](R)-PK11195 tumor uptake increased from 3 days to 1 week, and decreased at 2 weeks after cell inoculation, as opposed to the [18F]FDG uptake, which showed a slight decrease in uptake at 1 week and increased uptake at 2 weeks. In the control group, no significant differences occurred in tracer uptake over time. Tumor uptake of both radiopharmaceuticals is more expressed in tumor edge regions, with greater intensity at 2 weeks, as demonstrated by [11C](R)-PK11195 autoradiography and immunofluorescence with TSPO antibodies and CD86 pro-inflammatory phenotype. CONCLUSION: The [11C](R)-PK11195 was able to identify heterogeneous tumor inflammation in a murine model of breast cancer and the uptake varied according to tumor size. Together with the glycolytic marker [18F]FDG, molecular imaging with [11C](R)-PK11195 may provide a better characterization of inflammatory responses in cancer.

In Vitro Study of Cytotoxic Mechanisms of Alkylphospholipids and Alkyltriazoles in Acute Lymphoblastic Leukemia Models.

This study investigates the efficacy of miltefosine, alkylphospholipid, and alkyltriazolederivative compounds against leukemia lineages. The cytotoxic effects and cellular and molecular mechanisms of the compounds were investigated. The inhibitory potential and mechanism of inhibition of cathepsins B and L, molecular docking simulation, molecular dynamics and binding free energy evaluation were performed to determine the interaction of cathepsins and compounds. Among the 21 compounds tested, C9 and C21 mainly showed cytotoxic effects in Jurkat and CCRF-CEM cells, two human acute lymphoblastic leukemia (ALL) lineages. Activation of induced cell death by C9 and C21 with apoptotic and necrosis-like characteristics was observed, including an increase in annexin-V+propidium iodide-, annexin-V+propidium iodide+, cleaved caspase 3 and PARP, cytochrome c release, and nuclear alterations. Bax inhibitor, Z-VAD-FMK, pepstatin, and necrostatin partially reduced cell death, suggesting that involvement of the caspase-dependent and -independent mechanisms is related to cell type. Compounds C9 and C21 inhibited cathepsin L by a noncompetitive mechanism, and cathepsin B by a competitive and noncompetitive mechanism, respectively. Complexes cathepsin-C9 and cathepsin-C21 exhibited significant hydrophobic interactions, water bridges, and hydrogen bonds. In conclusion, alkyltriazoles present cytotoxic activity against acute lymphoblastic lineages and represent a promising scaffold for the development of molecules for this application.

Gender differences in the association between adverse events in childhood or adolescence and the risk of premature mortality.

To examine, by gender, the relationship between adverse events in childhood or adolescence and the increased risk of early mortality (before 80 years). The study sample included 941 participants of the English Longitudinal Study of Aging who died between 2007 and 2018. Data on socioeconomic status, infectious diseases, and parental stress in childhood or adolescence were collected at baseline (2006). Logistic regression models were adjusted by socioeconomic, behavioral and clinical variables. Having lived with only one parent (OR 3.79; p = 0.01), overprotection from the father (OR 1.12; p = 0.04) and having had an infectious disease in childhood or adolescence (OR 2.05; p = 0.01) were risk factors for mortality before the age of 80 in men. In women, overprotection from the father (OR 1.22; p < 0.01) was the only risk factor for mortality before the age of 80, whereas a low occupation of the head of the family (OR 0.58; p = 0.04) and greater care from the mother in childhood or adolescence (OR 0.86; p = 0.03) were protective factors. Independently of one's current characteristics, having worse socioeconomic status and health in childhood or adolescence increased the risk of early mortality in men. Parental overprotection increased the risk of early mortality in both sexes, whereas maternal care favored longevity in women.