-
Development (Cambridge, England) Jul 2024Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by...
Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach utilizing both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7bp substitution mutation results in massive perturbation of the Tinman regulatory network orchestrating dorsal musculature, manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation.
PubMed: 38958007
DOI: 10.1242/dev.202355 -
Therapeutic Apheresis and Dialysis :... Jul 2024This retrospective study aimed to evaluate the 30 and 60-day survival of critically ill patients with COVID-19 and AKI.
INTRODUCTION
This retrospective study aimed to evaluate the 30 and 60-day survival of critically ill patients with COVID-19 and AKI.
METHODS
Inflammatory and biochemical biomarkers, length of intensive care unit (ICU) stay and mortality at Day 30 and Day 60 after ICU admission were analyzed. A total of 44 patients treated with continuous renal replacement therapy (CRRT) with cytokine adsorber (CA group) were compared to 58 patients treated with CRRT alone (non-CA group).
RESULTS
Patients in CA group were younger, had better preserved kidney function prior to the beginning of CRRT and had higher levels of interleukin-6. There were no statistically significant differences in their comorbidities and in other measured biomarkers between the two groups. The number of patients who died 60 days after ICU admission was statistically significantly higher in non-CA group (p = 0.029).
CONCLUSION
Treatment with CRRT and cytokine adsorber may have positively influenced 60-day survival in our COVID-19 ICU patients with AKI.
PubMed: 38958006
DOI: 10.1111/1744-9987.14182 -
Journal of Minimal Access Surgery Jul 2024Minimally invasive liver resection (MILR) is performed for other gastrointestinal applications. At our centre, all liver resections are systematically performed using a...
INTRODUCTION
Minimally invasive liver resection (MILR) is performed for other gastrointestinal applications. At our centre, all liver resections are systematically performed using a minimally invasive approach. This study aimed to describe our experience in minimising open surgery and emphasised the importance of minimally invasive surgery.
PATIENTS AND METHODS
We retrospectively reviewed 260 patients who underwent liver surgery and compared the surgical outcomes between the open and MILR groups.
RESULTS
A total of 154 patients (68%) underwent MILR. The proportion of patients who underwent prior abdominal surgery and resection was higher in the open surgery group. However, the proportion of patients with liver cirrhosis was similar between the two groups. The MILR group was superior in terms of operative time, blood loss, Pringle manoeuvre rate and mean hospital stay. In addition, major complication and bile leak rates were lower in the MILR group. No significant differences in the tumour size, number of lesions or underlying liver pathology were observed between the two groups.
CONCLUSION
Acceptable outcomes can be achieved even when the minimally invasive approach is considered the primary option for all patients who require liver resection. Minimally invasive tools are necessary for the modern practice of liver surgery; therefore, laparoscopic or robotic surgery should be included in the armamentarium of liver surgeons.
PubMed: 38958005
DOI: 10.4103/jmas.jmas_377_23 -
Acta Psychiatrica Scandinavica Jul 2024Attention deficit hyperactivity disorder (ADHD) medication has proven effective for treating ADHD in adults, nonetheless previous studies have shown high rates of...
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) medication has proven effective for treating ADHD in adults, nonetheless previous studies have shown high rates of medication discontinuation.
OBJECTIVE
To assess drug survival and identify risk factors associated with discontinuation of ADHD medication.
METHODS
A nationwide registry-based cohort study in Danish adults who redeemed a prescription for ADHD medication for the first time between 2010 and 2015. All patients were followed for 5 years from the first redeemed prescription. Discontinuation was defined as a gap of 12 months between redemptions. Logistic regression analysis with odds ratio (OR) and Kaplan Meier analysis were used to examine risk factors (sex, age, socioeconomic status, substance use disorders, and comorbidities) associated with discontinuation.
RESULTS
Twenty three thousand nine-hundred and sixteen patients with ADHD were identified. The 5-year overall drug survival was 29% in women vs. 23.5% in men. The risk of medication discontinuation was significantly higher in men compared to women, OR 1.26 (95% CI 1.19-1.34, p < 0.001). Adults aged 31-50 years had a significantly decreased risk of medication discontinuation compared to adults aged 18-30 years, OR 0.57 (95% CI 0.53-0.61, p < 0.001). Switching ADHD medication two times or three times or more significantly decreased the risk of discontinuation; OR 0.53 (95% CI 0.49-0.56, p < 0.001) and OR 0.26 (95% CI 0.23-0.30, p < 0.001), respectively. Substance use disorders and certain comorbidities were associated with medication discontinuation. Eating disorders, OR 0.71 (95% CI 0.64-0.78, p < 0.001), intellectual disabilities, OR 0.65 (95% CI 0.59-0.73, p < 0.001) and sleep disorders, OR 0.42 (95% CI 0.37-0.49, p < 0.001) were associated with continuation of ADHD medication.
CONCLUSIONS
The 5-year overall drug survival was longer in women compared to men. Women with ADHD; adults aged 31-50; and patients with comorbid eating disorder; intellectual disability; sleep disorder and medication switching were individually associated with continuation of ADHD medication. Various factors were associated with medication discontinuation. Discontinuation should be acknowledged as a common phenomenon in patients with ADHD and calls for increased attention from the treatment responsible prescriber or team. Moreover, our findings suggest that timely, frequent medication switching, or temporary regimens may indeed represent optimal management strategies for a significant proportion of the ADHD population.
PubMed: 38958004
DOI: 10.1111/acps.13724 -
Health Services Research Jul 2024To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania.
OBJECTIVE
To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania.
DATA SOURCES AND STUDY SETTING
We analyzed data from the Pennsylvania cancer registry (2010-2018) for adult Medicaid beneficiaries aged 21-64 newly diagnosed with a solid tumor. To ascertain Medicaid and managed care status around diagnosis, we linked the cancer registry to statewide hospital-based facility records collected by an independent state agency (Pennsylvania Health Care Cost Containment Council).
STUDY DESIGN
We leveraged a natural experiment arising from county-level variation in mandatory MMC in Pennsylvania. Using a stacked difference-in-differences design, we compared changes in the probability of late-stage cancer diagnosis among those residing in counties that newly transitioned to mandatory managed care to contemporaneous changes among those in counties with mature MMC programs.
DATA COLLECTION/EXTRACTION METHODS
N/A.
PRINCIPAL FINDINGS
Mandatory MMC was associated with a reduced probability of late-stage cancer diagnosis (-3.9 percentage points; 95% CI: -7.2, -0.5; p = 0.02), particularly for screening-amenable cancers (-5.5 percentage points; 95% CI: -10.4, -0.6; p = 0.03). We found no significant changes in late-stage diagnosis among non-screening amenable cancers.
CONCLUSIONS
In Pennsylvania, the implementation of mandatory MMC for adult Medicaid beneficiaries was associated with earlier stage of diagnosis among newly diagnosed cancer patients with Medicaid, especially those diagnosed with screening-amenable cancers. Considering that over half of the sample was diagnosed with late-stage cancer even after the transition to mandatory MMC, Medicaid programs and managed care organizations should continue to carefully monitor receipt of cancer screening and design strategies to reduce barriers to guideline-concordant screening or diagnostic procedures.
PubMed: 38958003
DOI: 10.1111/1475-6773.14348 -
Foodborne Pathogens and Disease Jul 2024Goats are often asymptomatic carriers of , including the foodborne pathogen Infections can have significant and economically detrimental health outcomes in both humans...
Goats are often asymptomatic carriers of , including the foodborne pathogen Infections can have significant and economically detrimental health outcomes in both humans and animals. The primary objective of this study was to estimate the prevalence of in U.S. goat herds. species were isolated from 106 of 3,959 individual animals and from 42 of 277 goat operations that participated in fecal sample collection as part of the National Animal Health Monitoring System Goat 2019 study. Weighted animal-level prevalence was 2.3% (SE = 0.5%) and operation prevalence was 13.0% (SE = 3.2%). Animal-level prevalence ranged widely from 0 to 70.0%, however, 52.4% of positive operations (22/42) had only a single isolate. was the most frequently isolated species (68.9%; 73/106), followed by (29.3%, 31/106). A total of 46.2% (36/78) of viable isolates were pan-susceptible to 8 antimicrobials. Resistance to tetracycline (TET) was observed in 44.9% (35/78) of isolates, while 12.8% (10/78) were resistant to ciprofloxacin (CIP) and nalidixic acid (NAL). Among all isolates, a single resistance profile CIP-NAL-TET was observed in 3.8% (3/78) of isolates. A total of 35 unique sequence types (STs) were identified, 11 of which are potentially new. Multiple STs were observed in 48.1% (13/27) of positive operations. Goats with access to surface water, operations reporting antibiotics in the feed or water (excluding ionophores and coccidiostats), and operations reporting abortions and without postabortion management tasks had significantly greater odds of being positive. This snapshot of the U.S. goat population enriches the limited pool of knowledge on species presence in U.S. goats.
PubMed: 38957999
DOI: 10.1089/fpd.2023.0080 -
Surgical Infections Jul 2024Sex differences exist in sepsis, but the commitment of neutrophils to these differences remains unclear. Neutrophil extracellular traps (NETs) function to remove...
Sex differences exist in sepsis, but the commitment of neutrophils to these differences remains unclear. Neutrophil extracellular traps (NETs) function to remove pathogens, yet excessive NETs release can contribute to organ damage. This study explores effects of the gender hormones on endotoxin-induced NETs using neutrophils from both male and female sources. Blood samples were collected from healthy volunteers. Isolated neutrophils were seeded in collagen-coated cell culture plates, and NETs were induced by lipopolysaccharide (LPS) treatment. After 15 minutes of LPS treatment, 17β-estradiol (0.03-272.4 ng/mL), testosterone enanthate (0.01-10 ng/mL), dimethyl sulfoxide, or ethanol (vehicle control) was added to the plates. These were incubated for three hours at 37°C with 5% CO. Neutrophil extracellular traps formation was assessed using immunofluorescence staining. Lipopolysaccharide-induced NETs formation was significantly greater in females than in males. In male-derived neutrophils, 17β-estradiol at above the blood concentrations significantly suppressed LPS-induced NETs. No effect was seen while using testosterone enanthate to NETs at any concentration. In female-derived neutrophils, 17β-estradiol, which was near to the highest concentration of non-pregnant women's blood, tended to increase NETs. Testosterone enanthate, which was near to female blood concentration, significantly promoted NETs. Sex differences existed in LPS-induced NETs of human neutrophil. In males, high concentrations of 17β-estradiol administration may have a suppressive effect on excessive NETs during infection. In females, endogenous gender hormones may promote NETs during infection. Sex differences in neutrophils may need to be considered in organ damage owing to NETs excess such as sepsis.
PubMed: 38957997
DOI: 10.1089/sur.2024.016 -
American Journal of Epidemiology Jul 2024Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged...
Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.
PubMed: 38957996
DOI: 10.1093/aje/kwae168 -
Surgical Infections Jul 2024The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA)...
The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m), normal BMI (18.5-24.9 kg/m), and high BMI (≥25.0 kg/m). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.
PubMed: 38957995
DOI: 10.1089/sur.2023.382 -
Circulation Research Jul 2024Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits....
BACKGROUND
Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling events in the subclass of brain ECs/EPCs for CCM lesion initiation and progression are unclear.
METHODS
Brain EC-specific CCM3-deficient () mice were generated by crossing mice with -CreER mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10× genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches.
RESULTS
Single-cell RNA-sequencing analyses from P10 0 mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier-associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6 0 brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in mice. Mechanistic studies suggested that Cav1/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins.
CONCLUSIONS
CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss-induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis.
PubMed: 38957991
DOI: 10.1161/CIRCRESAHA.123.324015