Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1.

Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 µg/mL; EC90 ranging from 0.102-4.160 µg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease.

Metataxonomic Identification of Microorganisms during the Coffee Fermentation Process in Colombian Farms (Cesar Department).

The metataxonomic diversity and microbial composition of microorganisms during the coffee fermentation process as well as their relationship with coffee quality were determined across 20 farms in the department of Cesar, Colombia, by sampling coffee fruits from Coffea arabica; Var. Castillo General®, Var. Colombia, and Var. Cenicafé 1. In each farm, the fruits were processed and the fermentation process took place between 10 and 42 h following this. Three samples of mucilage and washed coffee seeds were collected per farm during the fermentation process. The microorganisms present in the mucilage were identified using metataxonomic methods by amplifying the 16S rRNA gene for bacteria and ITS for fungi. The microorganisms' morphotypes were isolated and identified. The analysis of bacteria allowed for the identification of the following genera: Gluconobacter, Leuconostoc, Acetobacter, Frateuria, Pantoea, Pseudomonas, Tatumella, and Weisella, as well as unclassified enterobacteria; the Lactobacillacea and Secundilactobacillus families were only identified in the Var. Cenicafé 1. For fungi, the top 11 genera and families found included Hanseniaspora, Candida, Meyerozyma, Wickerhamomyces, Pichia, f-Saccharomycodaceae, f-Nectriciae, unclassified fungi, and Saccharomycetaceae, which were only found in Cenicafé 1. A total of 92% of the coffee samples obtained scored between 80.1 and 84.9, indicating "Very Good" coffee (Specialty Coffee Association (SCA) scale). Farms with the longest fermentation times showed better coffee attributes related to acidity, fragrance, and aroma. During coffee fermentation, there is a central microbiome. The differences between the microorganisms' genera could be influenced by the coffee variety, while the specific conditions of each farm (i.e., altitude and temperature) and its fermentation processes could determine the proportions of and interactions between the microbial groups that favor the sensory characteristics responsible for coffee cup quality.

A Secondary Traumatic Stress Reduction Program in Emergency Room Nurses.

Introduction: Secondary traumatic stress is highly prevalent among nurses, especially among nurses working within the emergency department (ED). Reducing healthcare worker secondary traumatic stress is important for ensuring the delivery of high quality, safe patient care. This paper reports on the development and implementation of a secondary traumatic stress reduction program. Methods: We used an adaption of a 5-week intervention based on the Accelerated Recovery Program to test whether there would be a reduction in secondary traumatic stress in a pilot sample of nine ED nurses. Outcomes were assessed using the Secondary Traumatic Stress Scale (STSS), Somatic Symptoms Scale (SSS), and Compassion Satisfaction subscale (CSS) measures. Results: Eight of nine nurses were able to complete at least three of the five sessions. Results indicate significant change in STSS (F[5,23] = 4.22, p = .007) and SSS (F[3,15] = 4.42, p = .02) scores, but not CSS (F[5,23] = 0.83, p = .54) scores. Pairwise comparisons revealed that the beneficial effects of the program happened early. For both STSS and SSS, scores at sessions 1 and 2 were generally higher than subsequent sessions. We also found a trend for continued effects on STSS at a four-month follow-up (t23 = 1.95, p = .064). Conclusion: Overall, results indicate the 5-week program was associated with a significant reduction in secondary traumatic stress and related somatic symptoms in healthcare workers.

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV.

BACKGROUND: Islatravir (MK-8591) is a novel nucleoside analog in development for the treatment and prevention of HIV-1 infection. Islatravir has potent antiviral activity and a long intracellular half-life. SETTING: A 3-panel, randomized, double-blind, placebo-controlled, multiple-dose study in 36 adults without HIV evaluated the safety, tolerability, and pharmacokinetics of islatravir after daily administration. METHODS: Islatravir or placebo was administered orally once daily for 42 days (5 mg) or 28 days (0.25 mg; 0.75 mg). Blood samples were taken at prespecified time points for pharmacokinetic analysis of islatravir (plasma) and islatravir-triphosphate (ISL-TP; peripheral blood mononuclear cells [PBMCs]). Rectal and vaginal tissue samples were also collected in a subset of participants. Safety and tolerability were evaluated throughout. RESULTS: The pharmacokinetics of islatravir were approximately dose proportional, with concentrations approaching a steady state between days 14 and 21 in plasma and by day 28 for ISL-TP in PBMCs. Plasma exposure accumulation was 1.5-fold to 1.8-fold, and ISL-TP exposure accumulation was ∼10-fold. The apparent terminal half-life of ISL-TP was 177-209 hours. The ISL-TP pharmacokinetic trough threshold-the minimal concentration required for efficacy-of 0.05 pmol/106 cells was achieved after a single administration at all dose levels. Rectal and vaginal tissue also exhibited potentially therapeutic concentrations. Islatravir was generally well tolerated at all doses. CONCLUSIONS: ISL-TP levels in PBMCs were above the threshold projected for antiviral efficacy against wild-type HIV after a single 0.25-mg dose. Multiple once-daily dosing of islatravir in adults without HIV was generally well tolerated up to doses of 5 mg administered for up to 6 weeks.

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of a Respiratory Syncytial Virus Neutralizing Monoclonal Antibody MK-1654 in Healthy Adults.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost. To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-in-human study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.

Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects.

PURPOSE: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib. METHODS: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1-4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study. RESULTS: A median tmax of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CLss/F 308.2 and 322.1 L/h; mean Vzτ/F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2 ng/mL and 49.5 ng/mL; AUClast 1086 ng h/mL and 1153 ng h/mL, and AUCtau 779 ng h/mL and 745 ng h/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%). CONCLUSIONS: Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.

Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir.

Doravirine is a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Due to the high prevalence of HIV-1 and hepatitis C virus (HCV) coinfection and coadministration of HIV-1 and HCV treatment, potential drug-drug interactions (DDIs) between doravirine and two HCV treatments were investigated in two phase 1 drug interaction trials in healthy participants. Trial 1 investigated the effect of multiple-dose doravirine and elbasvir + grazoprevir coadministration (N = 12), and trial 2 investigated the effect of single-dose doravirine and ledipasvir-sofosbuvir coadministration (N = 14). Doravirine had no clinically relevant effect on the pharmacokinetics of elbasvir, grazoprevir, ledipasvir, sofosbuvir, or the sofosbuvir metabolite GS-331007. Coadministration of elbasvir + grazoprevir with doravirine moderately increased doravirine area under the concentration-time curve from 0 to 24 h (AUC0-24), maximal concentration (Cmax), and concentration 24 h postdose (C24), with geometric least-squares mean ratio (GMR) with 90% confidence intervals (CI) of 1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively. Doravirine AUC0-∞, Cmax, and C24 values increased slightly following coadministration with ledipasvir-sofosbuvir (GMR [90% CI] of 1.15 [1.07, 1.24], 1.11 [0.97, 1.27], and 1.24 [1.13, 1.36], respectively). The modest increases in doravirine exposure are not clinically meaningful based on the therapeutic profile of doravirine. Effects are likely secondary to cytochrome P450 3A and P-glycoprotein inhibition by grazoprevir and ledipasvir, respectively. Coadministration of doravirine with elbasvir + grazoprevir or ledipasvir-sofosbuvir was generally well tolerated. Clinically relevant DDIs are not expected to occur between doravirine and elbasvir-grazoprevir or ledipasvir-sofosbuvir at the therapeutic doses.

Impact of a Diabetes Risk Score on Lifestyle Education and Patient Adherence (IDEA) in Prediabetes: A Multisite Randomized Controlled Trial.

BACKGROUND: To evaluate whether knowledge of a personalized Diabetes Risk Score (DRS) improved performance in a 12-week lifestyle change program for prediabetes. METHODS: Randomized subjects at four clinics provided samples for a DRS at baseline, 12, and 24 weeks. The intervention group received scores at each point, whereas the control group only received this information at 12 and 24 weeks. Outcomes included attendance and changes in weight, abdominal circumference, blood pressure, fasting glucose, hemoglobin A1c, cholesterol, and risk score. RESULTS: Baseline characteristics were similar in the groups (n = 192) and within risk-stratified subgroups. At 12 weeks, there were no differences in outcomes, with mean weight loss of 4.61 kg in the intervention group and 4.43 kg in the control group (p = 0.79). Both groups were given 12-week risk scores, with previously unseen baseline scores for the control group. The control group continued to lose additional weight (1.21 kg) by 24 weeks, whereas the intervention group regained previously lost weight (0.33 kg) (p = 0.04). CONCLUSIONS: The knowledge of a single baseline personalized DRS did not affect performance in a lifestyle modification program. However, the knowledge of an improvement in risk score, and the timing of this information, may impact further adherence.

Adherencia a la quimioterapia y radioterapia en pacientes oncológicos: una revisión de la literatura / No disponible

Objetivo: Realizar una revisión de la literatura sobre la adherencia a la quimioterapia y a la radioterapia para el cáncer, por los altos costos biopsicosociales y culturales que acarrean y que están relacionados con bajas tasas de adherencia. Método: se realizó una búsqueda de la literatura en bases de datos especializadas utilizando las palabras clave. Resultados: Debido a que existe un porcentaje significativo de pacientes que no se adhieren a los tratamientos oncológicos y a que las consecuencias de no hacerlo pueden desencadenar un mayor riesgo de muerte o progresión de la enfermedad, es fundamental abordar este tema y para esto tener en cuenta las diferentes variables de tipo biológico, psicológico y social que influyen en la conducta de adherencia o no adherencia a los tratamientos, entre ellas la experimentación de efectos secundarios, la motivación, la capacidad de toma de decisiones, el estado emocional, la autonomía y la filosofía de vida de cada paciente. Esta investigación contribuye a que el personal de salud tenga más elementos para abordar esta problemática y así sus intervenciones sean más efectivas pudiendo incrementar la adherencia en los pacientes. Conclusiones: La adherencia es un constructo multifactorial y multideterminado, ampliamente estudiado en tratamientos no oncológicos (p.e. SIDA) y hay poca investigación que avale la eficacia de las intervenciones psicológicas para abordar la no adherencia y promover la adherencia a tratamientos oncológicos (AU)

Objective: To review in databases the relevant literature of adherence to chemotherapy and radiotherapy for cancer; which bring high biological, psychological, social and cultural costs and have been related to lower adherence rates. Method: A search in different databases was performed to identify relevant articles related to the key words. Results: A significant percentage of patients do not adhere to cancer treatments and the consequences of not doing it can unleash in a major risk of death or disease progression, then it is essential to approach this topic and take into account different variables of biological, psychological and social impact on the behavior of adherence or not adherence to the treatments; including the side effects, motivation, decision-making ability, emotional condition, autonomy and life philosophy of each patient. This research contributes to the health staff have more elements to approach this problem and so his interventions are more effective being able to increase the patient´s adherence. Conclusions: Adherence is a multifactorial and multi-determined construct, which has been extensively studied in non cancer treatments (e.g. AIDS) and there is few investigation that supports the efficacy of the psychological interventions to approach not adherence and to promote the adherence to cancer treatments (AU)

Diagnosis and testing in bronchiolitis: a systematic review.

BACKGROUND: The diagnosis of bronchiolitis is based on typical history and results of a physical examination. The indications for and utility of diagnostic and supportive laboratory testing (eg, chest x-ray films, complete blood cell counts, and respiratory syncytial virus testing) are unclear. OBJECTIVES: To review systematically the data on diagnostic and supportive testing in the management of bronchiolitis and to assess the utility of such testing. DESIGN: In conjunction with an expert panel, we generated admissibility criteria and derived relevant terms to search the literature published from 1980 to November 2002 in MEDLINE and the Cochrane Collaboration Database of Controlled Clinical Trials. Trained abstractors completed detailed data collection forms for each article. We summarized the data in tables after performing data integrity checks. RESULTS: Of the 797 abstracts identified, we present evidence from 82 trials that met our inclusion criteria (17 are primary articles on diagnosis of bronchiolitis and 65are reports of treatment or prevention trials). Numerous studies demonstrate that rapid respiratory syncytial virus tests have acceptable sensitivity and specificity, but no data show that respiratory syncytial virus testing affects clinical outcomes in typical cases of the disease. Seventeen studies presented chest x-ray film data. Abnormalities on chest x-ray films ranged from 20% to 96%. Insufficient data exist to show that chest x-ray films reliably distinguish between viral and bacterial disease or predict severity of disease. Ten studies included complete blood cell counts, but most did not present specific results. In one study, white blood cell counts correlated with radiologically defined disease categories of bronchiolitis. CONCLUSIONS: A large number of studies include diagnostic and supportive testing data. However, these studies do not define clear indications for such testing or the impact of testing on relevant patient outcomes. Given the high prevalence of this disease, prospective studies of the utility of such testing are needed and feasible.