Clinical Impact of Supplementation with Pasteurized Donor Human Milk by High-Temperature Short-Time Method versus Holder Method in Extremely Low Birth Weight Infants: A Multicentre Randomized Controlled Trial.

Nosocomial infections are a frequent and serious problem in extremely low birth weight (ELBW) infants. Donor human milk (DHM) is the best alternative for feeding these babies when mother's own milk (MOM) is not available. Recently, a patented prototype of a High-Temperature Short-Time (HTST) pasteurizer adapted to a human milk bank setting showed a lesser impact on immunologic components. We designed a multicentre randomized controlled trial that investigates whether, in ELBW infants with an insufficient MOM supply, the administration of HTST pasteurized DHM reduces the incidence of confirmed catheter-associated sepsis compared to DHM pasteurized with the Holder method. From birth until 34 weeks postmenstrual age, patients included in the study received DHM, as a supplement, pasteurized by the Holder or HTST method. A total of 213 patients were randomized; 79 (HTST group) and 81 (Holder group) were included in the analysis. We found no difference in the frequency of nosocomial sepsis between the patients of the two methods-41.8% (33/79) of HTST group patients versus 45.7% (37/81) of Holder group patients, relative risk 0.91 (0.64-1.3), p = 0.62. In conclusion, when MOM is not available, supplementing during admission with DHM pasteurized by the HTST versus Holder method might not have an impact on the incidence of catheter-associated sepsis.

Diferencias neuropsicológicas en la enfermedad de Alzheimer en función de la edad de presentación / Neuropsychological differences in Alzheimer's disease depending on the age of onset

Introducción La enfermedad de Alzheimer (EA) es la forma más común de demencia entre las personas mayores. La enfermedad de Alzheimer de inicio precoz (EAIP) se ha definido como una demencia debido a EA que se presenta antes de la edad arbitrariamente establecida de 65 años. De los pacientes con EA precoz, 50% debutan con síntomas atípicos y muestran alteraciones neuropsicológicas diferentes de aquellos pacientes que debutan más tarde. Estas atipias conllevan un retraso en el diagnóstico y en el inicio del tratamiento. Métodos Seleccionamos retrospectivamente 359 pacientes con diagnóstico de probable demencia por EA. Subdividimos a los pacientes en tres grupos atendiendo a la edad de aparición de la enfermedad: EAIP, menores de 65 años; EA de inicio tardío (EAIT; entre 65 y 80); y EA de inicio muy tardío (EAIMT; definido como edad de inicio mayor de 80 años) y comparamos sus resultados neuropsicológicos. Resultados Los pacientes de EA con una edad de inicio más joven puntuaron peor en atención, función ejecutiva y habilidades visuoespaciales, mientras que los pacientes de mayor edad puntuaron peor en tareas de memoria y lenguaje. Los pacientes de inicio muy tardío se diferenciaron de los de inicio tardío en un mayor deterioro de la fluidez semántica y la denominación. Conclusión Aunque la edad de 65 años podría corresponder a un punto de separación arbitrario entre la forma precoz y la forma de inicio más tardío de la EA, nuestro estudio demuestra que existen diferencias significativas entre estos grupos desde un punto de vista neuropsicológico. Sin embargo, estas diferencias parecen seguir una tendencia lineal con la edad, en lugar de representar cuadros clínicos fundamentalmente distintos. (AU)

Introduction Early-onset Alzheimer's disease (EOAD) has been defined as a dementia due to AD presenting before the arbitrarily established age of 65 (as opposed to late-onset Alzheimer's disease or LOAD). There is still little research about other age sub-groups, the use of so-called senile dementia has been banished, usually including it within the late-onset Alzheimer's dementia. To the extent of our knowledge, there are no studies comparing the neuropsychological features of very-late-onset patients with early and late-onset ones. Methods We retrospectively selected 359 patients with a diagnosis of probable AD dementia. We subdivided patients into three groups attending to the age of onset of the disease: early-onset AD (EOAD; younger than 65 years old), late-onset AD (LOAD; between 65 and 80) and very-late-onset AD (VLOAD; defined here as onset age older than 80), and then we compared their neuropsychological results. Results AD patients with a younger age at onset scored worse on attention, executive function and visuospatial skills, while older-onset patients scored worse in memory tasks and language. Patients with a very-late-onset differed from the late-onset ones in a greater impairment of semantic fluency and naming. Conclusion Although the point of separation between EOAD and later-onset forms of EA at the age of 65 is an arbitrary one, our study shows that there are significant differences between these groups from a neuropsychological point of view. However, these differences do seem to follow a linear trend with age, rather than representing fundamentally distinct clinical pictures. (AU)

Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review.

INTRODUCTION: Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges from prenatal to adult. The disease is characterised by an elevation of methylmalonic acid (MMA) and homocysteine and a decreased production of methionine. The aim is to review existing scientific literature of all late onset cblC patients in terms of clinical symptoms, diagnosis, and outcome. METHODS: A bibliographic database search was undertaken in PubMed (MEDLINE) complemented by a reference list search. We combined search terms regarding cblC disease and late onset. Two review authors performed the study selection, data extraction and quality assessment. RESULTS: Of the sixty-five articles included in this systematic review, we collected a total of 199 patients. The most frequent clinical symptoms were neuropathy/myelopathy, encephalopathy, psychiatric symptoms, thrombotic microangiopathy, seizures, kidney disease, mild to severe pulmonary hypertension with heart failure and thrombotic phenomena. There were different forms of supplementation used in the different studies collected and, within these studies, some patients received several treatments sequentially and/or concomitantly. The general outcome was: 64 patients recovered, 78 patients improved, 4 patients did not improve, or the disease progressed, and 12 patients died. CONCLUSIONS: Most scientific literature regarding the late onset cblC disease comes from case reports and case series. In most cases treatment initiation led to an improvement and even recovery of some patients. The lack of complete recovery underlines the necessity for increased vigilance in unclear clinical symptoms for cblC disease.

Late-onset Wilson Disease in a Patient Followed-up for Nonalcoholic Fatty Liver Disease.

A 73-year-old woman was referred to our hospital for persistent liver dysfunction. When the patient was 45 years old, her youngest sister had been diagnosed with Wilson disease (WD). The patient therefore underwent several family screening tests, all of which were unremarkable. She had an annual medical checkup and was diagnosed with liver dysfunction and fatty liver at 68 years old. A liver biopsy and genetic testing were performed, and she was diagnosed with WD; chelation therapy was then initiated. In patients with hepatic disorders and a family history of WD, multiple medical examinations should be conducted, as the development of WD is possible regardless of age.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Impact of Treatment with Ustekinumab on Severe Infections in a Patient with Uncontrolled Psoriasis and Late-Onset Combined Primary Immunodeficiency: Case Report.

A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn's disease was attended in the Regional Hospital of Presidente Prudente and HC-FMUSP, São Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to the failure of other treatments (phototherapy, oral acitretin) for psoriasis and a Psoriasis Area Severity Index >10. We evaluated the impact of treatment with ustekinumab on severe infectious diseases in a patient with uncontrolled psoriasis and LOCID followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, cultures of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation; pathogenic variants in genetic sequencing, and clinically significant variants in the whole exome for primary immunodeficiencies were not detected. The main infections before and after treatment with ustekinumab were chronic sinusitis and gastroenteritis. The patient was infected with COVID-19, dengue (twice) and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence the susceptibility of the patient with LOCID to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn's disease.

Compared Profile of Late-Onset Versus Childhood-Onset ADHD: A Case-Control Study Among Treatment-Seeking Adult Patients.

OBJECTIVE: To compare the characteristics of childhood-onset versus late-onset Attention Deficit Hyperactivity Disorder (ADHD) in a sample of treatment-seeking patients. METHOD: Among total of 101 adult patients who were recently diagnosed for ADHD, using the Diagnostic Interview for Adult ADHD (DIVA 2.0), 56 subjects exhibited childhood-onset ADHD, versus 45 displayed late-onset ADHD. Both groups were compared according to their sociodemographic, clinical, and neuropsychological features, providing crude (OR) and adjusted odds ratios (aOR), and their 95% confidence intervals [95% CI]. RESULTS: Compared to late-onset ADHD, patients with childhood-onset had a lower educational score, (OR = 0.52; 95% CI [0.35, 0.76]), a greater score of impulsivity (aOR = 1.09; 95% CI [1.03, 1.16]), an increased number of hyperactive-impulsive ADHD symptoms (aOR = 1.9; 95% CI [1.46, 2.47]), and higher rates childhood trauma (aOR = 1.07; 95% CI [1.01, 1.13]), cannabis use disorder (aOR = 1.07; 95% CI [1.01, 1.13]), and working memory impairment. No difference was observed concerning age, sex, psychiatric symptoms, quality of life, and autonomy. CONCLUSION: Childhood-onset adult ADHD displayed a more severe profile, relative to late-onset ADHD.

Korean Ginseng Berry Extract Enhances the Male Steroidogenesis Enzymes In Vitro and In Vivo.

PURPOSE: Testosterone hormonal replacement is the most commonly prescribed solution for men with reproductive issues; however, this treatment has various drawbacks. Hence, the identification of a natural product that promotes steroidogenesis is urgently needed. Ginseng is a popular traditional medicine. This study aimed to investigate steroidogenic effects of Korean ginseng berry extract (GBE; Panax ginseng C.A. Meyer) in vitro and in vivo. MATERIALS AND METHODS: In vitro model, mouse Leydig cells were treated with varying concentrations of GBE, and the levels of steroidogenesis-related genes and proteins and testosterone were measured using western blotting, qRT-PCR, and enzyme-linked immunosorbent assay (ELISA). Similarly, in an in vivo model using lipopolysaccharide-injected C57BL/6J mice, expression of steroidogenesis-related genes and proteins and testosterone levels were analyzed. Additionally, sleep deprivation was used to simulate common life stressors related to late-onset hypogonadism (LOH) and the natural effects of aging. Mice were fed sham or GBE before being subjected to paradoxical sleep deprivation. RESULTS: In vitro, GBE induced steroidogenic effects by increasing the levels of enzymes associated with steroidogenesis, steroidogenic acute regulatory protein (STAR), CYP11A1, and CYP17A1. In vivo, GBE significantly increased mRNA and protein levels of steroidogenic enzymes. Furthermore, the synthetic testosterone levels in mouse Leydig cell supernatants and blood sera were increased. In the sleep deprivation study, mice fed GBE showed increased testosterone production and survival under such stressful conditions. CONCLUSIONS: GBE increased mRNA and protein levels of steroidogenesis-related enzymes STAR, CYP11A1, and CYP17A1. These key enzymes induced the increased production of testosterone both in vivo and in vitro. Thus, GBE might be a promising therapeutic or additive nutritional agent for improving men's health by increasing steroidogenesis or improving LOH.

Effects of Aerobic Exercise Combined with Oyster Peptide Supplement on the Formation of CTX-induced Late-Onset Hypogonadism in Male Rats.

The purpose of this study is to investigate the effect of aerobic exercise (AE) training and/or oyster peptide (OP) supplementation on the formation of late-onset hypogonadism (LOH). AE training and/or OP supplement was performed during Cytoxan (CTX)-induced LOH formation in male SD rats for 6 consecutive weeks. Low dose of CTX could decrease mating times, the levels of luteinizing hormone (LH), total testosterone (TT), free testosterone (FT) in serum and TT, androgen receptor (AR), androgen binding protein (ABP), and glutathione peroxidase (GSH-Px) in testicle, but increase capture latency, mating latency, and malondialdehyde, and downregulate the mRNA expression of steroidogenic acute regulatory (StAR), P450 cholesterol side chain cleavage enzyme (P450scc), and StAR-related lipid transfer domain 7 (StARD7) in testicle. Every change was altered by AE training combined with OP supplement significantly, except for serum LH. Moreover, the effect of AE training combined with OP supplement was better than that of AE training on serum TT, FSH, testicular TT, mating latency, capture times, and mating times. AE training combined with OP supplement during CTX-induced LOH formation can prevent the LOH development by enhancing pituitary-gonads axis's function and reducing testicular oxidative stress to promote testosterone synthesis and spermatogenesis.

LC-MS/MS based untargeted lipidomics uncovers lipid signatures of late-onset preeclampsia.

The mechanisms underlying late-onset preeclampsia (LOPE) remain unknown. Metabolic disturbances have been implicated as a primary factor in LOPE development. Lipids have been shown to have great clinical value in recent years. This study aimed to use lipidomics to provide evidence for the etiology and potential therapeutic approaches for LOPE. Twenty patients with LOPE and 20 healthy controls were enrolled in this study. Placental lipidomic data were acquired using liquid chromatographymass spectrometry (LC-MS/MS), and the data were analyzed by weighted gene correlation network analysis (WGCNA) and statistical methods. Of 1508 identified lipids, 226 were differentially expressed between the LOPE and control groups. In the LOPE group, the abundance of most unsaturated triglycerides (TG) increased, whereas that of other lipids, including phosphatidylcholine (PC), sphingomyelin, and phosphatidylserine (PS) increased. The WGCNA implied that the correlation network module of lipids was highly related to clinical traits. Pathway analysis revealed that these dysregulated lipids are closely related to glycerophospholipid metabolism. Lipidomics may help identify the pathogenesis underlying placental dysfunction in LOPE patients and provide potential therapeutic targets in the future.

A novel HADHA variant associated with an atypical moderate and late-onset LCHAD deficiency.

Background: Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare inherited disease caused by pathogenic variants of HADHA gene. Along with signs common to fatty acid oxidation defects (FAOD), specific retina and heart alterations are observed. Because long-chain fatty acid oxidation is selectively affected, supplementations with short/medium-chain fats represent energetic sources bypassing the enzymatic blockade. Here, we report on an atypical presentation of the disease. Methods: Clinical features were described with medical explorations including ophthalmic and cardiac examination. Biological underlying defects were investigated by measurements of biochemical metabolites and by fluxomic studies of mitochondrial ß-oxidation. Whole exome sequencing and molecular validation of variants confirmed the diagnosis. Results: The patient has developed at nine years an unlabeled maculopathy, and at 28 years, an acute cardiac decompensation without any premise. Blood individual acylcarnitine analysis showed a rise in hydroxylated long-chain fatty acids and fluxomic studies validated enzyme blockade consistent with LCHADD. Genetic analysis revealed the common p.(Glu510Gln) variant in HADHA, in trans with a novel variant c.1108G > A, p.(Gly370Arg) located in the NAD binding domain. Patient pathology was responsive to triheptanoin supplementation. Conclusion: This atypical LCHADD form report should encourage the early assessment of biochemical and genetic testing as a specific management is recommended (combination with fast avoidance, low fat-high carbohydrate diet, medium-even-chain triglycerides or triheptanoin supplementation).

Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.

OBJECTIVES: To present the very long-term follow up of patients with cobalamin A (cblA) deficiency. METHODS: A retrospective case series of adult (>16 years) patients with molecular or enzymatic diagnosis of cblA deficiency. RESULTS: We included 23 patients (mean age: 27 ± 7.6 years; mean follow-up: 24.9 ± 7.6 years). Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%). Eight patients presented with chronic symptoms, and one had an adult-onset mild cblA deficiency. Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13). Initial management consisted of protein restriction (57%), B12 (17%), or both (26%). The main long-term problems were intellectual disability (39%) and renal failure (30%). However, 56.5% of the patients were living independently. Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12. CONCLUSIONS: We provide a detailed picture of the long-term outcome of a series of adult cblA patients, mostly diagnosed before the enzymatic and molecular era. We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay. In addition, we describe a patient with a milder adult-onset form. Early B12 supplementation seems to protect from severe renal insufficiency.

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS.

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

Daily mocha coffee intake and psycho-cognitive status in non-demented non-smokers subjects with subcortical ischaemic vascular disease.

Coffee intake has been recently associated with better cognition and mood in mild vascular cognitive impairment (mVCI). As tobacco can reduce the caffeine half-life, we excluded smokers from the original sample. Hamilton Depression Rating Scale (HDRS), mini-mental state examination (MMSE), Stroop Colour-Word Interference Test (Stroop), activities of daily living (ADL0) and instrumental ADL were the outcome measures. Significant differences were observed in higher consumption groups (moderate intake for HDRS; high intake for MMSE and Stroop) compared to the other groups, as well as in age and education. With age, education and coffee used as independent predictors, and HDRS, Stroop and MMSE as dependent variables, a correlation was found between age and both MMSE and Stroop, as well as between education and MMSE and between HDRS and Stroop; coffee intake negatively correlated with HDRS and Stroop. Higher coffee consumption was associated with better psycho-cognitive status among non-smokers with mVCI.

Late-onset Stargardt disease.

PURPOSE: To report a case of late-onset Stargardt disease, discuss the differential diagnosis, and review the role of vitamin A supplementation in Stargardt disease. OBSERVATIONS: A 60-year-old man presented with blurry vision in the right eye for the past two years. Current medications included a daily multivitamin containing vitamin A and age-related eye disease study vitamins. Examination revealed bilateral macular atrophy and scattered yellow flecks which were intensely hyperautofluorescent. Fluorescein angiography revealed a dark choroid. Full-field electroretinogram showed normal rod and cone responses, and genetic testing revealed two pathogenic ABCA4 gene variations confirming the diagnosis of late-onset Stargardt disease. CONCLUSIONS: Stargardt disease is typically described in young patients but may develop later in adulthood and masquerade as age-related macular degeneration and a number of other conditions. Though the evidence is limited, there is concern that high-dose vitamin A supplementation could lead to progression of Stargardt disease. Avoidance of high-dose vitamin A supplementation should be discussed with Stargardt disease patients.

Disentangling early and late onset of psychosis in women: identifying new targets for treatment.

Women present a second peak of incidence of psychosis during the menopausal transition, partially explained by the loss of estrogen protection conferred during the reproductive years. In view of the lack of studies comparing sociodemographic, biological, and clinical variables and neurocognitive performance between women with early onset of psychosis (EOP) and those with late onset of psychosis (LOP), our aim was to characterize both groups in a large sample of 294 first-episode psychosis (FEP) patients and 85 healthy controls (HC). In this cross-sectional study, the participants were interviewed to gather information on sociodemographic variables. We assessed laboratory features of interest and conducted a clinical assessment of psychopathological symptoms and neurocognitive abilities. From the latter, we derived a global cognitive functioning score. Analysis of covariance (ANCOVA) was used to compare EOP and LOP groups, and each group with age-comparable HC. EOP women were more frequently single and unemployed than HC age peers. While cholesterol levels in LOP women were higher than those in EOP women, no statistically significant differences were found in leptin levels. Women with LOP presented with less severe negative symptoms and higher cognitive processing speed scores than women with EOP. Cannabis and alcohol use was greater in EOP than in LOP women. Within the total FEP group, there was a history of significantly more recent traumatic events than in the HC group. Women with EOP and LOP show several sociodemographic and clinical differences, which may be valuable for planning personalized treatment.

Testosterone supplementation and bone parameters: a systematic review and meta-analysis study.

BACKGROUND: The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the object of an intense debate. METHODS: All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect of TRT on different bone parameters were considered. RESULTS: Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6 weeks. TRT improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-controlled RTCs showed a positive effect of TRT only at lumber spine and when trials included only hypogonadal patients at baseline (total testosterone < 12 nM). The effects on aBMD were more evident in subjects with lower T levels at baseline and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at endpoint contributed to aBMD improvement. TRT was associated with a significant reduction of bone resorption markers in observational but not in controlled studies. CONCLUSION: TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when the duration is long enough to allow the anabolic effect of T and estrogens on bone metabolism to take place.

[Potential mechanisms of Jiarong Tablets in the treatment of late-onset hypogonadism in men: An exploration based on network pharmacology].

OBJECTIVE: To study the therapeutic targets and related signaling pathways of Jiarong Tablets (JRT) in the treatment of late-onset hypogonadism (LOH) in males by network pharmacology, and further analyze its potential action mechanism. METHODS: Using the Chinese Medicine System Pharmacology Analysis Platform (TCMSP), we obtained the active ingredients and therapeutic targets of JRT, disease targets of LOH through the GeneCards and OMIM databases, and drug-disease common targets, followed by drawing a Vennny's diagram of the common targets. We constructed a protein-protein interaction (PPI) network of the common targets using STRING and an intersection network of JRT active ingredients-LOH-targets with Cytoscape 3.7.2, performed GO bio-functional and KEGG enrichment analyses of the common targets using the R-Language software, and identified the potential signaling pathways of JRT acting on LOH. RESULTS: Totally, we obtained 80 bioactive ingredients from JRT and 64 common targets of LOH, with IL-6, INS, AKT1, JUN and MAPK8 as the core targets in the order of the frequency occurrences. GO and KEGG analyses showed that these targets mainly involved the MAPK, HIF-1, Ras and ErbB signaling pathways. CONCLUSION: JRT acts on LOH with multiple targets, through multiple routes and at multiple levels, which is related to the expression of testosterone synthetase, oxidative stress and apoptosis of Leydig cells.

Sepsis treatment options identified by 10-year study of microbial isolates and antibiotic susceptibility in a level-four neonatal intensive care unit.

AIM: This observational study investigated the microbiology of blood culture-positive sepsis episodes and susceptibility to empiric antibiotics in early-onset sepsis (EOS) and late-onset sepsis (LOS) in a level-four neonatal intensive care unit (NICU) from 2010 to 2019. METHODS: It was based on patient records and data that Oslo University Hospital, Norway, routinely submitted to the Norwegian Neonatal Network database. Clinical data were merged with blood culture results, including antibiotic susceptibility. RESULTS: We studied 5249 infants admitted to the NICU 6321 times and identified 324 positive blood cultures from 287 infants, with 30 EOS and 305 LOS episodes. Frequent causative agents for EOS were group B streptococci (33.3%), Escherichia coli (20.0%) and Staphylococcus aureus (16.7%). All were susceptible to empiric ampicillin and gentamicin. LOS was most frequently caused by coagulase-negative staphylococci (CONS) (73.8%), Staphylococcus aureus (15.7%) and Enterococci (6.9%). CONS, Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella and Enterobacter represented 91.9% of LOS episodes and were susceptible to vancomycin and cefotaxime (96.1%), vancomycin and gentamicin (97.0%) and cloxacillin and gentamicin (38.1%). CONCLUSION: Empiric treatment with ampicillin and gentamicin was adequate for EOS. Combining vancomycin and gentamicin may be a safer alternative to cefotaxime for LOS, as this reduces exposure to broad-spectrum antibiotics.

A gene-environment interplay between omega-3 supplementation and APOE ε4 provides insights for Alzheimer's disease precise prevention amongst high-genetic-risk population.

BACKGROUND AND PURPOSE: The present study aimed to explore whether and how omega-3 (ω-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk. METHODS: A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE ε4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of ω-3 supplementation with APOE ε4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score. RESULTS: Individuals who progress to AD during the follow-up tend to take a shorter duration of ω-3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term ω-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω-3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores. CONCLUSIONS: Long-term ω-3 intake may have a role in AD prevention in genetically at-risk populations.