A comparative in vitro study on the effect of SGLT2 inhibitors on chemosensitivity to doxorubicin in MCF-7 breast cancer cells.

Cancer frequently develops resistance to the majority of chemotherapy treatments. This study aimed to examine the synergistic cytotoxic and antitumor effects of SGLT2 inhibitors, specifically Canagliflozin (CAN), Dapagliflozin (DAP), Empagliflozin (EMP), and Doxorubicin (DOX), using in vitro experimentation. The precise combination of CAN+DOX has been found to greatly enhance the cytotoxic effects of doxorubicin (DOX) in MCF-7 cells. Interestingly, it was shown that cancer cells exhibit an increased demand for glucose and ATP in order to support their growth. Notably, when these medications were combined with DOX, there was a considerable inhibition of glucose consumption, as well as reductions in intracellular ATP and lactate levels. Moreover, this effect was found to be dependent on the dosages of the drugs. In addition to effectively inhibiting the cell cycle, the combination of CAN+DOX induces substantial modifications in both cell cycle and apoptotic gene expression. This work represents the initial report on the beneficial impact of SGLT2 inhibitor medications, namely CAN, DAP, and EMP, on the responsiveness to the anticancer properties of DOX. The underlying molecular mechanisms potentially involve the suppression of the function of SGLT2.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota.

OBJECTIVE: To contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. PATIENTS AND METHODS: A validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. RESULTS: Two hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. CONCLUSION: The incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

Ehrlichia chaffeensis Co-Opts Phagocytic Hemocytes for Systemic Dissemination in the Lone Star Tick, Amblyomma americanum.

INTRODUCTION: Hematophagous arthropods can acquire and transmit several pathogens of medical importance. In ticks, the innate immune system is crucial in the outcome between vector-pathogen interaction and overall vector competence. However, the specific immune response(s) elicited by the immune cells known as hemocytes remains largely undefined in Ehrlichia chaffeensis and its competent tick vector, Amblyomma americanum. METHODS: We utilized injection of clodronate liposome to deplete tick granulocytes combined with infection with E. chaffeensis to demonstrate their essential role in microbial infection. RESULTS: Here, we show that granulocytes, professional phagocytic cells, are integral in eliciting immune responses against commensal and pathogen infection. The chemical depletion of granulocytes led to decreased phagocytic efficiency of tissue-associated hemocytes. We demonstrate that E. chaffeensis can infect circulating hemocytes, and both cell-free plasma and hemocytes from E. chaffeensis-infected ticks can establish Ehrlichia infection in recipient ticks. Lastly, we provide evidence to show that granulocytes play a dual role in E. chaffeensis infection. Depleting granulocytic hemocytes increased Ehrlichia load in the salivary gland and midgut tissues. In contrast, granulocyte depletion led to a reduced systemic load of Ehrlichia. CONCLUSION: This study has identified multiple roles for granulocytic hemocytes in the control and systemic dissemination of E. chaffeensis infection.

Ticks without borders: Microbial communities of immature Neotropical tick species parasitizing migratory landbirds along northern Gulf of Mexico.

The long-distance, seasonal migrations of birds make them an effective ecological bridge for the movement of ticks. The introduction of exotic tick species to new geographical regions can lead to the emergence of novel tick-borne pathogens or the re-emergence of previously eradicated ones. This study assessed the prevalence of exotic tick species parasitizing resident, short-distance, and long-distance songbirds during spring and autumn at stopover sites in the northern Gulf of Mexico using the mitochondrial 12S rDNA gene. Birds were captured for tick collection from six different sites from late August to early November in both 2018 and 2019. The highest number of ticks were collected in the 2019 season. Most ticks were collected off the Yellow-breasted Chat (Icteria virens) and Common Yellowthroat (Geothlypis trichas), and 54% of the total ticks collected were from Grand Chenier, LA. A high throughput 16S ribosomal RNA sequencing approach was followed to characterize the microbial communities and identify pathogenic microbes in all tick samples. Tick microbial communities, diversity, and community structure were determined using quantitative insight into microbial ecology (QIIME). The sparse correlations for compositional data (SparCC) approach was then used to construct microbial network maps and infer microbial correlations. A total of 421 individual ticks in the genera Amblyomma, Haemaphysalis, and Ixodes were recorded from 28 songbird species, of which Amblyomma and Amblyomma longirostre was the most abundant tick genus and species, respectively. Microbial profiles showed that Proteobacteria was the most abundant phylum. The most abundant bacteria include the pathogenic Rickettsia and endosymbiont Francisella, Candidatus Midichloria, and Spiroplasma. BLAST analysis and phylogenetic reconstruction of the Rickettsia sequences revealed the highest similarities to pathogenic spotted and non-spotted fever groups, including R. buchneri, R. conorii, R. prowazekii, R. bellii, R. australis, R. parkeri, R. monacensis, and R. monteiroi. Permutation multivariate analysis of variance revealed that the relative abundance of Francisella and Rickettsia drives microbial patterns across the tick genera. We also observed a higher percentage of positive correlations in microbe-microbe interactions among members of the microbial communities. Network analysis suggested a negative correlation between a) Francisella and Rickettsia and, b) Francisella and Cutibacterium. Lastly, mapping the distributions of bird species parasitized during spring migrations highlighted geographic hotspots where migratory songbirds could disperse ticks and their pathogens at stopover sites or upon arrival to their breeding grounds, the latter showing means dispersal distances from 421-5003 kilometers. These findings strongly highlight the potential role of migratory birds in the epidemiology of tick-borne pathogens.

Tick bite-induced Alpha-Gal Syndrome and Immunologic Responses in an Alpha-Gal Deficient Murine Model.

Introduction: Alpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to α-gal antigens and elevate the levels of α-gal specific IgE. However, the precise mechanism by which tick bites influence the hosts immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism. Methods: Lone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined. Results: Our results showed a significant increase in the titer of total IgE, IgG1, and α-gal IgG1 antibodies in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge in Am. americanum -sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed that Am. americanum bites direct mouse immunity toward Th2 and facilitate host sensitization to the α-gal antigen, while Am. maculatum did not. Conclusion: This study supports the hypothesis that specific tick species may increase the risk of developing α-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.

Tick salivary glycans - a sugar-coated tick bite.

Ticks are hematophagous arthropods that transmit disease-causing pathogens worldwide. Tick saliva deposited into the tick-bite site is composed of an array of immunomodulatory proteins that ensure successful feeding and pathogen transmission. These salivary proteins are often glycosylated, and glycosylation is potentially critical for the function of these proteins. Some salivary glycans are linked to the phenomenon of red meat allergy - an allergic response to red meat consumption in humans exposed to certain tick species. Tick salivary glycans are also invoked in the phenomenon of acquired tick resistance wherein non-natural host species exposed to tick bites develop an immune response that thwarts subsequent tick feeding. This review dwells on our current knowledge of these two phenomena, thematically linked by salivary glycans.

Hepatoprotective effects of bioactive compounds from traditional herb Tulsi (Ocimum sanctum Linn) against galactosamine-induced hepatotoxicity in rats.

Ocimum sanctum L. (Tulsi; Family: libiaceae), also known as "The Queen of herbs" or "Holy Basil," is an omnipresent, multipurpose plant that has been used in folk medicine of many countries as a remedy against several pathological conditions, including anticancer, antidiabetic, cardio-protective, antispasmodic, diaphoretic, and adaptogenic actions. This study aims to assess O. sanctum L.'s hepatoprotective potential against galactosamine-induced toxicity, as well as investigate bioactive compounds in each extract and identify serum metabolites. The extraction of O. sanctum L as per Ayurveda was simultaneously standardized and quantified for biochemical markers: rutin, ellagic acid, kaempferol, caffeic acid, quercetin, and epicatechin by HPTLC. Hepatotoxicity was induced albino adult rats by intra-peritoneal injection of galactosamine (400 mg/kg). The quantified hydroalcoholic and alcoholic extract of O. sanctum L (100 and 200 mg/kg body weight/day) were compared for evaluation of hepatoprotective potential, which were assessed in terms of reduction in histological damage, change in serum enzymes such as AST, ALT, ALP and increase TBARS. Twenty chemical constituents of serum metabolites of O. sanctum were identified and characterized based on matching recorded mass spectra by GC-MS with those obtained from the library-Wiley/NIST. We evaluated the hepatoprotective activity of various fractions of hydroalcoholic extracts based on the polarity and investigated the activity at each phase (hexane, chloroform, and ethyl acetate) in vitro to determine how they affected the toxicity of CCL4 (40 mM) toward Chang liver cells. The ethyl acetate fraction of the selected plants had a higher hepatoprotective activity than the other fractions, so it was used in vacuum liquid chromatography (VLC). The ethyl acetate fraction contains high amounts of rutin (0.34% w/w), ellagic acid (2.32% w/w), kaempferol (0.017% w/w), caffeic acid (0.005% w/w), quercetin (0.038% w/w), and epicatechin (0.057% w/w) which are responsible for hepatoprotection. In comparison to standard silymarin, isolated bioactive molecules displayed the most significant hepatoprotective activity in Chang liver cells treated to CCl4 toxicity. The significant high hepatoprotection provided by standard silymarin ranged from 77.6% at 100 µg/ml to 83.95% at 200 µg/ml, purified ellagic acid ranged from 70% at 100 µg/ml to 81.33% at 200 µg/ml, purified rutin ranged from 63.4% at 100 µg/ml to 76.34% at 200 µg/ml purified quercetin ranged from 54.33% at 100 µg/ml to 60.64% at 200 µg/ml, purified epicatechin ranged from 53.22% at 100 µg/ml to 65.6% at 200 µg/ml, and purified kaempferol ranged from 52.17% at 100 µg/ml to 60.34% at 200 µg/ml. These findings suggest that the bioactive compounds in O. sanctum L. have significant protective effects against galactosamine-induced hepatotoxicity.

Ehrlichia chaffeensis co-opts phagocytic hemocytes for systemic dissemination in the Lone Star tick, Amblyomma americanum.

Hematophagous arthropods can acquire and transmit several pathogens of medical importance. In ticks, the innate immune system is crucial in the outcome between vector-pathogen interaction and overall vector competence. However, the specific immune response(s) elicited by the immune cells known as hemocytes remains largely undefined in Ehrlichi a chaffeensis and its competent tick vector, Amblyomma americanum . Here, we show that granulocytes, professional phagocytic cells, are integral in eliciting immune responses against commensal and pathogen infection. The chemical depletion of granulocytes led to decreased phagocytic efficiency of tissues-associated hemocytes. We demonstrate E. chaffeensis can infect circulating hemocytes, and both cell-free plasma and hemocytes from E. chaffeensis- infected ticks can establish Ehrlichia infection in recipient ticks. Lastly, we provide evidence to show granulocytes play a dual role in E. chaffeensis infection. Depleting granulocytic hemocytes increased Ehrlichia load in the salivary gland and midgut tissues. In contrast, granulocyte depletion led to a reduced systemic load of Ehrlichia . This study has identified multiple roles for granulocytic hemocytes in the control and systemic dissemination of E. chaffeensis infection.

Altered Pharmacokinetics Parameters of Vancomycin in Patients with Hematological Malignancy with Febrile Neutropenia, a Bayesian Software Estimation.

The pharmacokinetics of vancomycin vary significantly between specific groups of patients, such as critically ill patients and patients with hematological malignancy (HM) with febrile neutropenia (FN). Recent evidence suggests that the use of the usual standard dose of antibiotics in patients with FN may not offer adequate exposure due to pharmacokinetic variability (PK). Therefore, the purpose of this study is to assess the effect of FN on AUC0-24 as a key parameter for vancomycin monitoring, as well as to determine which vancomycin PK parameters are affected by the presence of FN using Bayesian software PrecisePK in HM with FN. This study was carried out in King Abdulaziz Medical City. All adult patients who were admitted to the Princess Norah Oncology Center PNOC between 1 January and 2017 and 31 December 2020, hospitalized and received vancomycin with a steady-state trough concentration measured before the fourth dose, were included. During the trial period, 297 patients received vancomycin during their stay at the oncology center, 217 of them meeting the inclusion criteria. Pharmacokinetic parameters were estimated for the neutropenic and non-FN patients using the precise PK Bayesian platform. The result showed that there was a significant difference (p < 0.05) in vancomycin clearance Clvan, the volume of distribution at a steady-state Vdss, the volume of distribution for peripheral compartment Vdp, half-life for the elimination phase t½ß, and the first-order rate constant for the elimination process ß in FN compared to non-FN patients. Furthermore, AUC0-24 was lower for FN patients compared to non-FN patients, p < 0.05. FN has a significant effect on the PK parameters of vancomycin and AUC0-24, which may require specific consideration during the treatment initiation.

Intranasal cerium oxide nanoparticles improves locomotor activity and reduces oxidative stress and neuroinflammation in haloperidol-induced parkinsonism in rats.

Introduction: Cerium oxide nanoparticles (CONPs) have been investigated for their therapeutic potential in Parkinson's disease (PD) due to their potent and regenerative antioxidant activity. In the present study, CONPs were used to ameliorate the oxidative stress caused by free radicals in haloperidol-induced PD in rats following intranasal administration. Method: The antioxidant potential of the CONPs was evaluated in vitro using ferric reducing antioxidant power (FRAP) assay. The penetration and local toxicity of the CONPs was evaluated ex-vivo using goat nasal mucosa. The acute local toxicity of intranasal CONPs was also studied in rat. Gamma scintigraphy was used to assess the targeted brain delivery of CONPs. Acute toxicity studies were performed in rats to demonstrate safety of intranasal CONPs. Further, open field test, pole test, biochemical estimations and brain histopathology was performed to evaluate efficacy of intranasal CONPs in haloperidol-induced PD rat model. Results: The FRAP assay revealed highest antioxidant activity of prepared CONPs at a concentration of 25 µg/mL. Confocal microscopy showed deep and homogenous distribution of CONPs in the goat nasal mucus layers. No signs of irritation or injury were seen in goat nasal membrane when treated with optimized CONPs. Scintigraphy studies in rats showed targeted brain delivery of intranasal CONPs and acute toxicity study demonstrated safety. The results of open field and pole test showed highly significant (p < 0.001) improvement in locomotor activity of rats treated with intranasal CONPs compared to untreated rats. Further, brain histopathology of treatment group rats showed reduced neurodegeneration with presence of more live cells. The amount of thiobarbituric acid reactive substances (TBARS) was reduced significantly, whereas the levels of catalase (CAT), superoxide dismutase (SOD), and GSH were increased significantly, while amounts of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) showed significant reduction after intranasal administration of CONPs. Also, the intranasal CONPs, significantly high (p < 0.001) dopamine concentration (13.93 ± 0.85 ng/mg protein) as compared to haloperidol-induced control rats (5.76 ± 0.70 ng/mg protein). Conclusion: The overall results concluded that the intranasal CONPs could be safe and effective therapeutics for the management of PD.

Urolithin A's Antioxidative, Anti-Inflammatory, and Antiapoptotic Activities Mitigate Doxorubicin-Induced Liver Injury in Wistar Rats.

Human colon microbiota produce a metabolite called urolithin A (URO A) from ellagic acid and linked compounds, and this metabolite has been demonstrated to have antioxidant, anti-inflammatory, and antiapoptotic activities. The current work examines the various mechanisms through which URO A protects against doxorubicin (DOX)-induced liver injury in Wistar rats. In this experiment, Wistar rats were administered DOX intraperitoneally (20 mg kg-1) on day 7 while given URO A intraperitoneally (2.5 or 5 mg kg-1 d-1) for 14 days. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) were measured. Hematoxylin and eosin (HE) staining was used to evaluate histopathological characteristics, and then antioxidant and anti-inflammatory properties were evaluated in tissue and serum, respectively. We also looked at how active caspase 3 and cytochrome c oxidase were in the liver. The findings demonstrated that supplementary URO A therapy clearly mitigated DOX-induced liver damage. The antioxidant enzymes SOD and CAT were elevated in the liver, and the levels of inflammatory cytokines, such as TNF-α, NF-kB, and IL-6, in the tissue were significantly attenuated, all of which complemented the beneficial effects of URO A in DOX-induced liver injury. In addition, URO A was able to alter the expression of caspase 3 and cytochrome c oxidase in the livers of rats that were subjected to DOX stress. These results showed that URO A reduced DOX-induced liver injury by reducing oxidative stress, inflammation, and apoptosis.

Sensitivity to imidacloprid insecticide varies among some social and solitary bee species of agricultural value.

Pollinator health risks from long-lasting neonicotinoid insecticides like imidacloprid has primarily focused on commercially managed, cavity-nesting bees in the genera Apis, Bombus, and Osmia. We expand these assessments to include 12 species of native and non-native crop pollinators of differing levels of body size, sociality, and floral specialization. Bees were collected throughout 2016 and 2017 from flowering blueberry, squash, pumpkin, sunflower and okra in south Mississippi, USA. Within 30-60 minutes of capture, bees were installed in bioassay cages made from transparent plastic cups and dark amber jars. Bees were fed via dental wicks saturated with 27% (1.25 M) sugar syrup containing a realistic range of sublethal concentrations of imidacloprid (0, 5, 20, or 100 ppb) that are often found in nectar. Bees displayed no visible tremors or convulsions except for a small sweat bee, Halictus ligatus, and only at 100ppb syrup. Imidacloprid shortened the captive longevities of the solitary bees. Tolerant bee species lived ~10 to 12 days in the bioassays and included two social and one solitary species: Halictus ligatus, Apis mellifera and Ptilothrix bombiformis (rose mallow bees), respectively. No other bee species tolerated imidacloprid as well as honey bees did, which exhibited no appreciable mortality and only modest paralysis across concentration. In contrast, native bees either lived shorter lives, experienced longer paralysis, or endured both. Overall, longevity decreased with concentration linearly for social bees and non-linearly for solitary species. The percentage of a bee's captive lifespan spent paralyzed increased logarithmically with concentration for all species, although bumble bees suffered longest. Of greatest concern was comparable debilitation of agriculturally valuable solitary bees at both low and high sublethal rates of imidacloprid.

Autonomic Cardiovascular Control in Health and Disease.

Autonomic neural control of the cardiovascular system is formed of complex and dynamic processes able to adjust rapidly to mitigate perturbations in hemodynamics and maintain homeostasis. Alterations in autonomic control feature in the development or progression of a multitude of diseases with wide-ranging physiological implications given the neural system's responsibility for controlling inotropy, chronotropy, lusitropy, and dromotropy. Imbalances in sympathetic and parasympathetic neural control are also implicated in the development of arrhythmia in several cardiovascular conditions sparking interest in autonomic modulation as a form of treatment. A number of measures of autonomic function have shown prognostic significance in health and in pathological states and have undergone varying degrees of refinement, yet adoption into clinical practice remains extremely limited. The focus of this contemporary narrative review is to summarize the anatomy, physiology, and pathophysiology of the cardiovascular autonomic nervous system and describe the merits and shortfalls of testing modalities available. © 2023 American Physiological Society. Compr Physiol 13:4493-4511, 2023.

Detection of Adverse Drug Reactions in COVID-19 Hospitalized Patients in Saudi Arabia: A Retrospective Study by ADR Prompt Indicators.

Seeking an alternative approach for detecting adverse drug reactions (ADRs) in coronavirus patients (COVID-19) and enhancing drug safety, a retrospective study of six months was conducted utilizing an electronic medical record (EMR) database to detect ADRs in hospitalized patients for COVID-19, using "ADR prompt indicators" (APIs). Consequently, confirmed ADRs were subjected to multifaceted analyses, such as demographic attribution, relationship with specific drugs and implication for organs and systems of the body, incidence rate, type, severity, and preventability of ADR. The incidence rate of ADRs is 37%, the predisposition of organs and systems to ADR is observed remarkably in the hepatobiliary and gastrointestinal systems at 41.8% vs. 36.2%, p < 0.0001, and the classes of drugs implicated in the ADRs are lopinavir-ritonavir 16.3%, antibiotics 24.1%, and hydroxychloroquine12.8%. Furthermore, the duration of hospitalization and polypharmacy are significantly higher in patients with ADRs at 14.13 ± 7.87 versus 9.55 ± 7.90, p < 0.001, and 9.74 ± 5.51 versus 6.98 ± 4.36, p < 0.0001, respectively. Comorbidities are detected in 42.5% of patients and 75.2%, of patients with DM, and HTN, displaying significant ADRs, p-value < 0.05. This is a symbolic study providing a comprehensive acquaintance of the importance of APIs in detecting hospitalized ADRs, revealing increased detection rates and robust assertive values with insignificant costs, incorporating the hospital EMR database, and enhancing transparency and time effectiveness.

Impact of Sleep Duration and Chronotype on Cardiac Structure and Function: The UK Biobank Study.

Sleep duration and chronotype have been associated with increased morbidity and mortality. We assessed for associations between sleep duration and chronotype on cardiac structure and function. UK Biobank participants with CMR data and without known cardiovascular disease were included. Self-reported sleep duration was categorized as short (<7 h/d), normal (7-9 h/d) and long (>9 h/d). Self-reported chronotype was categories as "definitely morning" or "definitely evening." Analysis included 3903 middle-aged adults: 929 short, 2924 normal and 50 long sleepers; with 966 definitely-morning and 355 definitely-evening chronotypes. Long sleep was independently associated with lower left ventricular (LV) mass (-4.8%, P = 0.035), left atrial maximum volume (-8.1%, P = 0.041) and right ventricular (RV) end-diastolic volume (-4.8%, P = 0.038) compared to those with normal sleep duration. Evening chronotype was independently associated with lower LV end-diastolic volume (-2.4%, P = 0.021), RV end-diastolic volume (-3.6%, P = 0.0006), RV end systolic volume (-5.1%, P = 0.0009), RV stroke volume (RVSV -2.7%, P = 0.033), right atrial maximal volume (-4.3%, P = 0.011) and emptying fraction (+1.3%, P = 0.047) compared to morning chronotype. Sex interactions existed for sleep duration and chronotype and age interaction for chronotype even after considering potential confounders. In conclusion, longer sleep duration was independently associated with smaller LV mass, left atrial volume and RV volume. Evening chronotype was independently associated with smaller LV and RV and reduced RV function compared to morning chronotype. Sex interactions exist with cardiac remodeling most evident in males with long sleep duration and evening chronotype. Recommendations for sleep chronotype and duration may need to be individualized based on sex.

Rickettsia parkeri hijacks tick hemocytes to manipulate cellular and humoral transcriptional responses.

Introduction: Blood-feeding arthropods rely on robust cellular and humoral immunity to control pathogen invasion and replication. Tick hemocytes produce factors that can facilitate or suppress microbial infection and pathogenesis. Despite the importance of hemocytes in regulating microbial infection, understanding of their basic biology and molecular mechanisms remains limited. Methods: Here we combined histomorphology and functional analysis to identify five distinct phagocytic and non-phagocytic hemocyte populations circulating within the Gulf Coast tick Amblyomma maculatum. Results and discussion: Depletion of phagocytic hemocytes using clodronate liposomes revealed their function in eliminating bacterial infection. We provide the first direct evidence that an intracellular tick-borne pathogen, Rickettsia parkeri, infects phagocytic hemocytes in Am. maculatum to modify tick cellular immune responses. A hemocyte-specific RNA-seq dataset generated from hemocytes isolated from uninfected and R. parkeri-infected partially blood-fed ticks generated ~40,000 differentially regulated transcripts, >11,000 of which were immune genes. Silencing two differentially regulated phagocytic immune marker genes (nimrod B2 and eater-two Drosophila homologs), significantly reduced hemocyte phagocytosis. Conclusion: Together, these findings represent a significant step forward in understanding how hemocytes regulate microbial homeostasis and vector competence.

The Bayesian-Based Area under the Curve of Vancomycin by Using a Single Trough Level: An Evaluation of Accuracy and Discordance at Tertiary Care Hospital in KSA.

The AUC0-24 is the most accurate way to track the vancomycin level while the Cmin is not an accurate surrogate. Most hospitals in Saudi Arabia are under-practicing the AUC-guided vancomycin dosing and monitoring. No previous work has been conducted to evaluate such practice in the whole kingdom. The current study objective is to calculate the AUC0-24 using the Bayesian dosing software (PrecisePK), identify the probability of patients who receive the optimum dose of vancomycin, and evaluate the accuracy and precision of the Bayesian platform. This retrospective study was conducted at King Abdulaziz medical city, Jeddah. All adult patients treated with vancomycin were included. Pediatric patients, critically ill patients requiring ICU admission, patients with acute renal failure or undergoing dialysis, and febrile neutropenic patients were excluded. The AUC0-24 was predicted using the PrecisePK platform based on the Bayesian principle. The two-compartmental model by Rodvold et al. in this platform and patients' dose data were utilized to calculate the AUC0-24 and trough level. Among 342 patients included in the present study, the mean of the estimated vancomycin AUC0-24 by the posterior model of PrecisePK was 573 ± 199.6 mg, and the model had a bias of 16.8%, whereas the precision was 2.85 mg/L. The target AUC0-24 (400 to 600 mg·h/L) and measured trough (10 to 20 mg/L) were documented in 127 (37.1%) and 185 (54%), respectively. Furthermore, the result demonstrated an increase in odds of AUC0-24 > 600 mg·h/L among trough level 15-20 mg/L group (OR = 13.2, p < 0.05) as compared with trough level 10-14.9 mg/L group. In conclusion, the discordance in the AUC0-24 ratio and measured trough concentration may jeopardize patient safety, and implantation of the Bayesian approach as a workable alternative to the traditional trough method should be considered.