Immunogenicity of High-Dose vs. MF59-adjuvanted vs. Standard Influenza Vaccine in Solid Organ Transplant Recipients: The STOP-FLU trial.

BACKGROUND The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so that new vaccination strategies are needed in this population. METHODS Adult SOT recipients from nine transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. High, with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least one vaccine strain at 28 days post-vaccination. Secondary outcomes included PCR-confirmed influenza and vaccine reactogenicity. RESULTS 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n=198; MF59-adjuvanted, n=205; high-dose, n=195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs. standard vaccine, 0.20 [97.5% CI 0.12-1]; p<0.001; difference in high-dose vs. standard vaccine, 0.24 [95% CI 0.16-1]; p<0.001; difference in MF59-adjuvanted vs. standard vaccine, 0.17 [97.5% CI 0.08-1]; p<0.001). Influenza occurred in 6% the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. TRIAL REGISTRATION Clinicaltrials.gov NCT03699839

Drosophila pacemaker neurons require G-protein signaling and GABAergic inputs to generate 24hr behavioral rhythms

Recent experiments indicate that intercellular signaling is important in generating accurate circadian rhythms. In Drosophila, the small ventral lateral neurons (s-LNvs) seem to be the dominant pacemaker neurons since they set the pace of the majority of other clock neurons in the brain, at least in constant darkness. Here I describe evidence that two independent G-protein signaling pathways in LNvs are required for 24hr rhythms. Reducing signaling in LNvs via the G-alpha subunit Gs, which signals via cAMP, or via the G-alpha subunit Go, which I show signals via Phospholipase 21c, lengthens the period of behavioral rhythms. In contrast, constitutively activating Gs or Go signaling in LNvs causes most flies to become arrhythmic. Using dissociated LNvs in culture, I found that Go signaling is required for the inhibitory effects of GABA on LNvs via the metabotropic GABAB-R3 receptor. Reducing GABAB-R3 expression in LNvs in vivo lengthens period. Although no clock neurons produce GABA, hyper-exciting GABAergic neurons disrupt behavioral rhythms and s-LNv molecular clocks. Therefore, I propose that s-LNvs require input signals, including GABA, to keep their molecular clocks running with a 24hr period

Drosophila Pacemaker Neurons Require G Protein Signaling and GABAergic Inputs to Generate Twenty-Four Hour Behavioral Rhythms

SummaryIntercellular signaling is important for accurate circadian rhythms. In Drosophila, the small ventral lateral neurons (s-LNvs) are the dominant pacemaker neurons and set the pace of most other clock neurons in constant darkness. Here we show that two distinct G protein signaling pathways are required in LNvs for 24 hr rhythms. Reducing signaling in LNvs via the G alpha subunit Gs, which signals via cAMP, or via the G alpha subunit Go, which we show signals via Phospholipase 21c, lengthens the period of behavioral rhythms. In contrast, constitutive Gs or Go signaling makes most flies arrhythmic. Using dissociated LNvs in culture, we found that Go and the metabotropic GABAB-R3 receptor are required for the inhibitory effects of GABA on LNvs and that reduced GABAB-R3 expression in vivo lengthens period. Although no clock neurons produce GABA, hyperexciting GABAergic neurons disrupts behavioral rhythms and s-LNv molecular clocks. Therefore, s-LNvs require GABAergic inputs for 24 hr rhythms

Comparison of claims data on hospitalization rates and repeat procedures in patients receiving a bowel preparation prior to colonoscopy

Objectives: To evaluate outcomes of colorectal screening using sodium picosulfate and magnesium citrate compared with other prescription bowel-preparation agents. Primary endpoints were rates of procedure-associated hospitalizations, diagnosis at hospitalization, and rates of early repeat screenings. Methods: This retrospective cohort study identified patients using the Truven Health Analytics MarketScan databases, which contain fully adjudicated, de-identified, medical- and prescription-drug claims, as well as demographic and enrollment information for individuals with commercial, Medicaid, and Medicare supplemental insurance coverage. Patients who had a colonoscopy or sigmoidoscopy over a 3-year period were identified using International Classification of Diseases Clinical Modification procedure codes, recorded on claims from physicians and facilities. First, screening colonoscopy was identified for each patient, and the study was limited to those patients who could be observed for ≥6 months before and 3 months after the screening procedure. Total number of hospitalizations and rates of early repeat screenings were evaluated for all patients who received sodium picosulfate and magnesium citrate and compared with those who received other bowel-preparation agents. Individual prescription medications that could affect the outcome of the cleansing agent were identified; further evaluations were made to establish whether patients had comorbid conditions, such as chronic kidney disease, cardiovascular disease, or psychiatric illness. Statistical methods included descriptive statistics, two-tailed t -tests, and multivariate logistic regression. Results: A total of 566,628 procedures were identified in the MarketScan databases and included in the study. Sodium picosulfate and magnesium citrate performed well in terms of safety outcomes, with no hospitalizations due to diagnosis of hyponatremia, dehydration, or other fluid disorders in the 10 days after procedure. Early repeat rates among sodium picosulfate and magnesium citrate patients were comparable with rates observed for all other cleansing agents. Conclusion: Outcomes of colorectal screening using sodium picosulfate and magnesium citrate were not significantly different compared with other prescription bowel-preparation agents

The Role of the FSH System in the Development and Progression of Prostate Cancer

Introduction It is likely that dysregulation of the follicle-stimulating hormone (FSH) system plays a significant role in the progression of abnormal prostate growth from benign prostatic hyperplasia (BPH) to hormone-dependent prostate cancer to castration-resistant prostate cancer (CRPC). This review will focus on the data supporting this role of FSH in prostate cancer, and begin to draw together evidence of the mechanisms by which the FSH system may be dysregulated. Finally, we will discuss the impact that pharmacologic androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone, also called luteinizing hormone-releasing hormone (GnRH/LHRH), receptor agonists and antagonists may have on the FSH system.1-5 Throughout this review, we use the term FSH system to encompass all aspects of FSH, including the synthesis, release, and circulating levels of FSH itself, as well as its receptor and receptor signaling

Mortality, healthcare resource utilization, and cost among Medicare beneficiaries with Clostridioides difficile infection with and without sepsis.

ObjectiveTo describe mortality, healthcare resource utilization (HRU), and costs among Medicare beneficiaries with primary Clostridioides difficile infection (pCDI) or recurrent CDI (rCDI), with and without sepsis.MethodsWe conducted a retrospective observational study of 100% Medicare Fee-for-Service claims from adults aged ⩾ 65 years with ⩾1 CDI episode between 1 January 2009 and 31 December 2017. Patients were continuously enrolled in Medicare Parts A/B/D 12 months before and up to 12 months after pCDI. ICD-9/10 codes defined CDI using ⩾1 inpatient claim, or ⩾1 outpatient claim plus ⩾1 claim for CDI treatment. The pCDI episode ended after 14 days without a CDI claim. rCDI episodes started within 8 weeks from the end of a previous CDI episode. ICD-9/10 codes identified all-cause sepsis over 12 month follow-up.ResultsOf 497,489 CDI patients, 41.0% (N = 203,888) had sepsis; 57.7% with sepsis died versus 32.4% without sepsis. Among patients with pCDI only (N = 345,893) or ⩾1 rCDI (N = 151,596), 39.2% and 45.1% suffered sepsis, respectively. All-cause hospitalizations were frequent for all cohorts (range: 81-99%). Among patients who died, those with sepsis versus without had more-frequent intensive care unit (ICU) use (pCDI: 29% versus 15%; rCDI: 65% versus 34%), longer hospital stays (pCDI: 12 versus 10 days; rCDI: 12 versus 9 days), and higher per-patient-per-month costs (pCDI: $34,841 versus$22,753; rCDI: $42,269 versus$25,047). In both cohorts, sepsis patients who survived had higher total costs and all-cause HRU than those without sepsis. All p &lt; 0.001 above.ConclusionsSepsis was common among Medicare beneficiaries with CDI. CDI patients with sepsis, especially after an rCDI, experienced higher mortality, HRU, and costs compared with those without sepsis

Performance of overnight on-call radiology residents in interpreting unenhanced abdominopelvic magnetic resonance imaging studies performed for pediatric right lower quadrant abdominal pain

BACKGROUND: Abdominopelvic magnetic resonance imaging (MRI) is increasingly being used to evaluate children with abdominal pain suspected of having acute appendicitis. At our institution, these examinations are preliminarily interpreted by radiology residents, especially when performed after hours. OBJECTIVE: To determine the accuracy of preliminary reports rendered by radiology residents in this setting. MATERIALS AND METHODS: Three hundred seventy-seven pediatric abdominopelvic MRI examinations were included. The preliminary (resident) and final (attending) radiology reports were coded as diagnosing acute appendicitis or no acute appendicitis. The concordance between resident and attending radiologist interpretations was calculated. Additionally, both resident and attending reports were compared to available surgical pathology or clinical follow-up data. RESULTS: Overall concordance rate for the diagnosis of acute appendicitis was 97.1%. Concordance for verified cases of acute appendicitis was 93.4%. Concordance rates did not differ by residents\u27 postgraduate year levels. When compared against surgical pathology or clinical follow-up data, residents demonstrated 91.2% sensitivity and 97.6% specificity. There was no statistically significant difference in the sensitivity or specificity of resident or attending radiologist interpretations. CONCLUSION: Radiology residents demonstrate high concordance with attending pediatric radiologists in their interpretations of pediatric abdominopelvic MRI for acute appendicitis. The diagnostic performances of residents and attendings were comparable