Leveraging opportunities for treatment/user simplicity (LOTUS): Navigating the current treatment landscape for achieving hepatitis C virus elimination among persons who inject drugs.

All-oral, direct-acting antivirals can cure hepatitis C virus (HCV) in almost all infected individuals; yet, many individuals with chronic HCV are not treated, and the incidence of acute HCV is increasing in some countries, including the United States. Strains on healthcare resources during the COVID-19 pandemic negatively impacted the progress toward the World Health Organization goal to eliminate HCV by 2030, especially among persons who inject drugs (PWID). Here, we present a holistic conceptual framework termed LOTUS (Leveraging Opportunities for Treatment/User Simplicity), designed to integrate the current HCV practice landscape and invigorate HCV treatment programs in the setting of endemic COVID-19: (A) treatment as prevention (especially among PWID), (B) recognition that HCV cure may be achieved with variable adherence with evidence supporting some forgiveness for missed doses, (C) treatment of all persons with active HCV infection (viremic), regardless of acuity, (D) minimal monitoring (MinMon) during treatment, and (E) rapid test and treat (TnT). The objective of this article is to review the current literature supporting each LOTUS petal; identify remaining gaps in knowledge or data; define the remaining barriers facing healthcare providers; and review evidence-based strategies for overcoming key barriers.

Phase I/II trial of BMS-986,205 and nivolumab as first line therapy in hepatocellular carcinoma.

BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC. METHODS: Adults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50-100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy. RESULTS: Eight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4-5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached. CONCLUSION: Combination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.

Corrected sinus node recovery time as a screening test in patients with typical atrial flutter post-ablation to predict pacemaker implantation / Tiempo de recuperación del nodo sinusal corregido como prueba de tamizaje en pacientes con aleteo atrial típico postablación para predecir la implantación de marcapasos

Abstract Objective: The objective of the study was to establish the prognostic value of CSNRT regarding the necessity for pacemaker implantation in patients with atrial flutter (AFL) post-ablation. Methods: This prospective cohort study, conducted at the National Institute of Cardiology "Ignacio Chavez" in Mexico City, assessed patients who had undergone ablation procedures to correct AFL, posterior to which an autonomic blockade was performed, and CSNRT was measured. Results: The sample for this investigation was 40 patients. These were subdivided into two study groups depending on their requirement of pacemaker implant post-ablation (Pacemaker P, No Pacemaker NP). Sinus node (SN) dysfunction was diagnosed in 13 (32.5%) of the 40 participants, 10 (71.43%) of which required a pacemaker implant, while only 4 participants (28.57%) with normal SN function required pacemakers. Ten out of the 14 patients (71.43%) who required a pacemaker had an elevated CSNRT > 500 ms (p ≤ 0.01). Post-ablation CSNRT mean was 383.54 ms ± 67.96 ms in the NP group versus 1972.57 ms ± 3423.56 ms in the P group. Furthermore, SN pause in the P group had a mean of 1.86 s ± 0.96 s versus the NP group with 1.196 s ± 0.52 s. Conclusion: CSNRT has the potential to be a quantitative prognostic tool for the assessment of future pacemaker implants in patients with AFL post-ablation. This could aid in the timely diagnosis of sinus node dysfunction, which could, in the long run, result in the reduction of cardiac functional capacity loss due to cardiac remodeling.

Resumen Objetivo: Establecer el valor pronóstico del TRNSC basado en la necesidad de marcapasos en pacientes diagnosticados con aleteo atrial, pos-ablación. Métodos: Este cohorte prospectivo, realizado en el Instituto Nacional de Cardiología "Ignacio Chávez" en la Ciudad de México, evaluó pacientes sometidos a ablación para corregir el aleteo atrial; se midió el TRNSC post bloqueo autonómico. Resultados: La muestra de 40 pacientes se subdividió en 2 grupos según su requerimiento de marcapasos posterior a la ablación (P y NP). Se diagnosticó disfunción del nodo sinusal en 13 participantes (32.5%), de los cuales 10 (71.43%) requirieron marcapasos en comparación a 4 (28.57%) con función normal. En el grupo P la pausa del nodo sinusal post-ablación tuvo una media de 1.86 ± 0.96 s versus el grupo NP con 1.196 ± 0.52 s. En relación con el TRNSC, el grupo NP tuvo una media de 383.54 ± 67.96 ms vs. 1972.57 ± 3423.56 ms en el grupo P. 10 pacientes (25%) obtuvieron un TRNSC > 500 ms, de los cuales 100% requirieron marcapasos; de los 14 pacientes que requirieron marcapasos 10 (71.43%) tenían un TRNSC elevado (p ≤ 0.01). Conclusiones: El TRNSC tiene el potencial de ser una herramienta de pronóstico cuantitativo para la necesidad de futuros implantes de marcapasos en pacientes con disfunción del nodo sinusal, resultado de aleteo atrial pos-ablación. Esto podría ayudar a diagnosticar más temprano una disfunción del nodo sinusal, resultando en la reducción de la pérdida a largo plazo de la función cardíaca como efecto de la remodelación.

Efectividad del consumo de Brownies de sangrecita y el nivel de hemoglobina en niños de una institución educativa inicial pública, Ica / Effectiveness of the consumption of sangrecita brownies and the hemoglobin level in children of the Initial Educational Institution Public, Ica

Según la OPS, los países desarrollados alcanzan un 11% de prevalencia de anemia, mientras que en los países en vías de desarrollo afecta al tercio poblacional, llegando a superar el 50% en el continente africano y asiático. El estudio tuvo como Objetivo: Analizar la efectividad del consumo de brownies de sangrecita sobre los niveles de hemoglobina en niños de la Institución Educativa Inicial Pública, Ica. Material y métodos: Para el desarrollo se utilizó la metodología de tipo cuasi experimental, nivel aplicativo y de enfoque cuantitativo. La población de estudio estuvo conformada por 100 niños, se realizó el descarte de anemia mediante el analizador de hemoglobina (hemo Q), micro cubetas, lancetas y demás implementos médicos. Para analizar los resultados se tuvo en consideración los valores normales emitidos por el Ministerio de Salud(MINSA) y se utilizaron fichas de control. Resultados: Se captó a 4 niños de la IEI Nº14 Mercedes Dibós de Camino al realizar el tamizaje inicial de anemia, quienes tenían un nivel de hemoglobina inferior a los valores normales de acuerdo a la normativa del MINSA; luego de consumir los brownies de sangrecita en un intervalo de 3 veces por semana durante 7 semanas se evidenció un incremento en sus niveles de hemoglobina respecto al tamizaje inicial. Conclusiones: El consumo de brownie de sangrecita es efectivo en el tratamiento de la anemia en los niños, incrementando su nivel de hemoglobina entre 1.9 g/dl a 2.3 g/dl

According to PAHO, developed countries reach an 11% prevalence of anemia, while in developing countries it affects one third of the population, reaching over 50% in the African and Asian continents. The study had the Objective: To analyze the effectiveness of the consumption of sangrecita brownies on hemoglobin levels in children of the Initial Educational Institution Public, Ica. Material and methods: A quasi-experimental methodology with a quantitative approach was used for the development of the study. The study population consisted of 100 children. Anemia was ruled out using the hemoglobin analyzer (hemoQ), micro cuvettes, lancets and other medical implements. To analyze the results, the normal values issued by MINSA were taken into consideration and control cards were used. Results:4 children from the IEI Nº14 Mercedes Dibós de Camino were caught during the initial screening for anemia, who had a hemoglobin level below the normal values according to MINSA regulations; but after consuming the blood brownies at an interval of 3 times per week for 7 weeks, an increase in their hemoglobin levels was evidenced with respect to the initial screening. Conclusion: The consumption of sangrecita brownie is effective in the treatment of anemia in children by increasing their hemoglobin level, the increase value was between 1.9 g/dl and 2.3 g/dl.Key Words:Anemia, sangrecita brownie, hemoglobin, fortification, children.

Evaluación del control del Asma en República Dominicana: una perspectiva clínica / Evaluation of Asthma Control in the Dominican Republic: a Clinical Perspective

Introducción: El asma es una patología respiratoria caracterizada por inflamación cró-nica y reversible de las vías aéreas. Esta se asocia con factores de riesgo modificables y no modificables que influyen sobre su control y exacerbaciones. En países como Puer-to Rico y Cuba, la prevalencia del asma es significativamente mayor a la global (22,8%, 23% y 6,6%, respectivamente).

Introduction: Asthma is a respiratory pathology characterized by chronic and reversible airway inflammation. It is associated with modifiable and non-modifiable risk factors that influence its control and exacerbations. In countries such as Puerto Rico (22.8 %) and Cuba (23 %), the prevalence of asthma is significantly higher than the global prevalence (6.6 %).

Tissue clearing and imaging approaches for in toto analysis of the reproductive system.

New microscopy techniques in combination with tissue clearing protocols and emerging analytical approaches have presented researchers with the tools to understand dynamic biological processes in a three-dimensional context. This paves the road for the exploration of new research questions in reproductive biology, for which previous techniques have provided only approximate resolution. These new methodologies now allow for contextualized analysis of far larger volumes than was previously possible. Tissue optical clearing and three-dimensional imaging techniques posit the bridging of molecular mechanisms, macroscopic morphogenic development, and maintenance of reproductive function into one cohesive and comprehensive understanding of the biology of the reproductive system. In this review, we present a survey of the various tissue clearing techniques and imaging systems, as they have been applied to the developing and adult reproductive system. We provide an overview of tools available for analysis of experimental data, giving particular attention to the emergence of AI-assisted methods and their applicability to image analysis. We conclude with an evaluation of how novel image analysis approaches which have been applied to other organ systems could be incorporated into future experimental evaluation of reproductive biology.

Corrected sinus node recovery time as a screening test in patients with typical atrial flutter post-ablation to predict pacemaker implantation.

OBJECTIVE: The objective of the study was to establish the prognostic value of CSNRT regarding the necessity for pacemaker implantation in patients with atrial flutter (AFL) post-ablation. METHODS: This prospective cohort study, conducted at the National Institute of Cardiology "Ignacio Chavez" in Mexico City, assessed patients who had undergone ablation procedures to correct AFL, posterior to which an autonomic blockade was performed, and CSNRT was measured. RESULTS: The sample for this investigation was 40 patients. These were subdivided into two study groups depending on their requirement of pacemaker implant post-ablation (Pacemaker P, No Pacemaker NP). Sinus node (SN) dysfunction was diagnosed in 13 (32.5%) of the 40 participants, 10 (71.43%) of which required a pacemaker implant, while only 4 participants (28.57%) with normal SN function required pacemakers. Ten out of the 14 patients (71.43%) who required a pacemaker had an elevated CSNRT > 500 ms (p ≤ 0.01). Post-ablation CSNRT mean was 383.54 ms ± 67.96 ms in the NP group versus 1972.57 ms ± 3423.56 ms in the P group. Furthermore, SN pause in the P group had a mean of 1.86 s ± 0.96 s versus the NP group with 1.196 s ± 0.52 s. CONCLUSION: CSNRT has the potential to be a quantitative prognostic tool for the assessment of future pacemaker implants in patients with AFL post-ablation. This could aid in the timely diagnosis of sinus node dysfunction, which could, in the long run, result in the reduction of cardiac functional capacity loss due to cardiac remodeling.

OBJETIVO: Establecer el valor pronóstico del TRNSC basado en la necesidad de marcapasos en pacientes diagnosticados con aleteo atrial, pos-ablación. MÉTODOS: Este cohorte prospectivo, realizado en el Instituto Nacional de Cardiología "Ignacio Chávez" en la Ciudad de México, evaluó pacientes sometidos a ablación para corregir el aleteo atrial; se midió el TRNSC post bloqueo autonómico. RESULTADOS: La muestra de 40 pacientes se subdividió en 2 grupos según su requerimiento de marcapasos posterior a la ablación (P y NP). Se diagnosticó disfunción del nodo sinusal en 13 participantes (32.5%), de los cuales 10 (71.43%) requirieron marcapasos en comparación a 4 (28.57%) con función normal. En el grupo P la pausa del nodo sinusal post-ablación tuvo una media de 1.86 ± 0.96 s versus el grupo NP con 1.196 ± 0.52 s. En relación con el TRNSC, el grupo NP tuvo una media de 383.54 ± 67.96 ms vs. 1972.57 ± 3423.56 ms en el grupo P. 10 pacientes (25%) obtuvieron un TRNSC > 500 ms, de los cuales 100% requirieron marcapasos; de los 14 pacientes que requirieron marcapasos 10 (71.43%) tenían un TRNSC elevado (p ≤ 0.01). CONCLUSIONES: El TRNSC tiene el potencial de ser una herramienta de pronóstico cuantitativo para la necesidad de futuros implantes de marcapasos en pacientes con disfunción del nodo sinusal, resultado de aleteo atrial pos-ablación. Esto podría ayudar a diagnosticar más temprano una disfunción del nodo sinusal, resultando en la reducción de la pérdida a largo plazo de la función cardíaca como efecto de la remodelación.

Reported adverse events related to use of hepatitis C virus direct-acting antivirals with opioids: 2017-2021.

INTRODUCTION: Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant use of opioids and DAAs. METHODS: AEs reported (July 28, 2017-December 31, 2021) with the administration of the DAAs glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir/voxilaprevir, and elbasvir/grazoprevir as suspect products were downloaded from the US Food and Drug Administration AE Reporting System Public Dashboard. The number of AE reports containing opioids (fentanyl, hydrocodone, oxycodone) as co-suspect products/concomitant products were counted and summarized by severity, reporting country and whether an outcome of death was reported. Overdose AEs were counted irrespective of opioid use, and changes over time were assessed. RESULTS: In total, 40 AEs were reported for DAAs and concomitant fentanyl use, 25 (62.5%) were in the USA, 35 (87.5%) were considered serious, and 14 (35.0%) resulted in death; and 626 were reported with concomitant oxycodone/hydrocodone use, 596 (95.2%) were in the USA, 296 (47.3%) were considered serious, and 28 (4.5%) resulted in death. There were 196 overdose AEs (32 [16%] deaths) declining from 2018 (N = 56) to 2021 (N = 29). CONCLUSIONS: Treating people with hepatitis C virus (HCV) infection who use drugs is key to achieving HCV elimination. Low numbers of DAA AE reports with opioids may provide reassurance to prioritize HCV treatment in this population. These data contribute to evidence supporting the continued scale-up of DAA treatment among people who use drugs to achieve HCV elimination goals.

Assessment of Drug-Drug Interaction Risk Between Intravenous Fentanyl and the Glecaprevir/Pibrentasvir Combination Regimen in Hepatitis C Patients Using Physiologically Based Pharmacokinetic Modeling and Simulations.

INTRODUCTION: An unsafe injection practice is one of the major contributors to new hepatitis C virus (HCV) infections; thus, people who inject drugs are a key population to prioritize to achieve HCV elimination. The introduction of highly effective and well-tolerated pangenotypic direct-acting antivirals, including glecaprevir/pibrentasvir (GLE/PIB), has revolutionized the HCV treatment landscape. Glecaprevir is a weak cytochrome P450 3A4 (CYP3A4) inhibitor, so there is the potential for drug-drug interactions (DDIs) with some opioids metabolized by CYP3A4, such as fentanyl. This study estimated the impact of GLE/PIB on the pharmacokinetics of intravenous fentanyl by building a physiologically based pharmacokinetic (PBPK) model. METHODS: A PBPK model was developed for intravenous fentanyl by incorporating published information on fentanyl metabolism, distribution, and elimination in healthy individuals. Three clinical DDI studies were used to verify DDIs within the fentanyl PBPK model. This model was integrated with a previously developed GLE/PIB PBPK model. After model validation, DDI simulations were conducted by coadministering GLE 300 mg + PIB 120 mg with a single dose of intravenous fentanyl (0.5 µg/kg). RESULTS: The predicted maximum plasma concentration ratio between GLE/PIB + fentanyl and fentanyl alone was 1.00, and the predicted area under the curve ratio was 1.04, suggesting an increase of only 4% in fentanyl exposure. CONCLUSION: The administration of a therapeutic dose of GLE/PIB has very little effect on the pharmacokinetics of intravenous fentanyl. This negligible increase would not be expected to increase the risk of fentanyl overdose beyond the inherent risks related to the amount and purity of the fentanyl received during recreational use.

Shorter Duration Hepatitis C Virus Treatment is Associated with Better Persistence to Prescription Refills in People Who Inject Drugs: A Real-World Study.

INTRODUCTION: Direct-acting antiviral (DAA) therapy is highly effective in curing hepatitis C virus (HCV) infection in people who inject drugs (PWID). Previous studies showed declining persistence to DAA therapy over the course of treatment. This study compares real-world medication persistence to prescription refills for 8- versus 12-week DAA in treatment-naïve PWID with chronic HCV with compensated cirrhosis or without cirrhosis. METHODS: Symphony Health's claims database was used to collect data from patients with chronic HCV aged ≥ 12 years who were prescribed 8- or 12-week DAA therapy between August 2017 and November 2020 and had a diagnosis of addicted drug use within 6 months prior to index date. Eligible patients had medical/pharmacy claims in the 6 months before and 3 months after the first index medication fill date (i.e., index date). Patients completing all refills (8-week = 1 refill, 12-week = 2 refills) were deemed persistent. The percentage of persistent patients in each group, and at each refill step, was determined; outcomes were also assessed in a subgroup of Medicaid-insured patients. RESULTS: This study assessed 7203 PWID with chronic HCV (8-week, 4002; 12-week, 3201). Patients prescribed 8-week DAA treatment were younger (42.9 ± 12.4 vs 47.5 ± 13.2, P < 0.001) and had fewer comorbidities (P < 0.001). Patients receiving 8- versus 12-week DAA had greater refill persistence (87.9% vs 64.4%, P < 0.001). Similar percentages of patients missed their first refill (8-week, 12.1% vs 12-week, 10.8%); nearly 25% of patients receiving 12-week DAA missed their second refill. After baseline characteristics were controlled, patients prescribed 8- versus 12-week DAA were more likely to be persistent (odds ratio [95% confidence interval] 4.3 [3.8, 5.0]). Findings in the Medicaid-insured subgroup were consistent. CONCLUSION: Patients prescribed 8- vs 12-week DAA therapy had significantly greater prescription refill persistence. Most nonpersistence was due to missed second refills, highlighting the potential benefit of shorter treatment durations in this population.

Kinematics and energetics of foraging behavior in Rice's whales of the Gulf of Mexico.

Rorqual foraging behavior varies with species, prey type and foraging conditions, and can be a determining factor for their fitness. Little is known about the foraging ecology of Rice's whales (Balaenoptera ricei), an endangered species with a population of fewer than 100 individuals. Suction cup tags were attached to two Rice's whales to collect information on their diving kinematics and foraging behavior. The tagged whales primarily exhibited lunge-feeding near the sea bottom and to a lesser extent in the water-column and at the sea surface. During 6-10 min foraging dives, the whales typically circled their prey before executing one or two feeding lunges. Longer duration dives and dives with more feeding-lunges were followed by an increase in their breathing rate. The median lunge rate of one lunge per dive of both animals was much lower than expected based on comparative research on other lunge-feeding baleen whales, and may be associated with foraging on fish instead of krill or may be an indication of different foraging conditions. Both animals spent extended periods of the night near the sea surface, increasing the risk for ship strike. Furthermore, their circling before lunging may increase the risk for entanglement in bottom-longline fishing gear. Overall, these data show that Rice's whale foraging behavior differs from other lunge feeding rorqual species and may be a significant factor in shaping our understanding of their foraging ecology. Efforts to mitigate threats to Rice's whales will benefit from improved understanding of patterns in their habitat use and fine-scale ecology.

Real-World Effectiveness of 8-Week Glecaprevir/Pibrentasvir in Treatment-Naïve, Compensated Cirrhotic HCV Patients.

INTRODUCTION: The EXPEDITION-8 clinical trial has demonstrated that treatment-naïve patients with compensated cirrhosis (TN/CC) of HCV genotypes 1-6 can achieve a 98% intent-to-treat sustained virologic response rate 12 weeks post-treatment with an 8-week glecaprevir/pibrentasvir (G/P) regimen. Further real-world evidence is needed to support the effectiveness of 8-week G/P in a clinical practice setting and to consolidate these treatment recommendations. The aim of this study is to contribute real-world evidence for the effectiveness of an 8-week G/P treatment in TN/CC patients with HCV genotypes 1-6. METHODS: Retrospective real-world data from 494 TN/CC patients with HCV genotypes 1-6 were collected between August 2017 to December 2020 from the Symphony Health Solutions administrative claims database. Demographic and clinical characteristics were collected at baseline. Patients were required to have a follow-up HCV ribonucleic acid level at least 8 weeks or more after the end of treatment. The percentage of patients achieving a sustained virologic response (SVR) is reported. RESULTS: The majority of patients were male (58%) and Caucasian (40%), with a mean age of 58 years; 74%, 12%, 12%, and 1% of patients were HCV genotype 1, 2, 3, and 4-6 infected, respectively. SVR was achieved in 95.5% of all patients. Across patient subgroups, SVR was achieved in 95.6% of patients with HCV genotype 3 and in 93% of HCV patients with a recent diagnosis of illicit drug use or abuse (within 6 months prior to G/P initiation). CONCLUSION: Early real-world evidence indicates high effectiveness of the 8-week G/P regimen in TN/CC patients of HCV genotypes 1-6 from a large US claims database.

Improving hepatitis C screening and access to treatment.

ABSTRACT: The rising prevalence of opioid use disorder and injection drug use has resulted in an increasing incidence of chronic hepatitis C virus (HCV) infection. Although older adults historically have represented the bulk of HCV infections in the United States, demographics have shifted and most new infections are presenting in younger patients. As a result, screening guidelines for HCV have evolved, moving toward a near-universal screening paradigm. Rates of screening and linkage to care remain low, attributed to the fact that underserved populations are disproportionately affected and often have limited access to specialty care. Collaborative models to treat HCV using primary care providers have been proposed to facilitate linkage to care and reduce transmission.

A phase I dose escalation, dose expansion and pharmacokinetic trial of gemcitabine and alisertib in advanced solid tumors and pancreatic cancer.

PURPOSE: Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion. METHODS: Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles. RESULTS: In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration. CONCLUSIONS: This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.

Acoustic localization, validation, and characterization of Rice's whale calls.

The recently named Rice's whale in the Gulf of Mexico is one of the most endangered whales in the world, and improved knowledge of spatiotemporal occurrence patterns is needed to support their recovery and conservation. Passive acoustic monitoring methods for determining spatiotemporal occurrence patterns require identifying the species' call repertoire. Rice's whale call repertoire remains unvalidated though several potential call types have been identified. This study uses sonobuoys and passive acoustic tagging to validate the source of potential call types and to characterize Rice's whale calls. During concurrent visual and acoustic surveys, acoustic-directed approaches were conducted to obtain visual verifications of sources of localized sounds. Of 28 acoustic-directed approaches, 79% led to sightings of balaenopterid whales, of which 10 could be positively identified to species as Rice's whales. Long-moan calls, downsweep sequences, and tonal-sequences are attributed to Rice's whales based on these matches, while anthropogenic sources are ruled out. A potential new call type, the low-frequency downsweep sequence, is characterized from tagged Rice's whale recordings. The validation and characterization of the Rice's whale call repertoire provides foundational information needed to use passive acoustic monitoring for better understanding and conservation of these critically endangered whales.

Impact of microstructure on cell behavior and tissue mechanics in collagen and dermal decellularized extra-cellular matrices.

Skin models are used for many applications such as research and development or grafting. Unfortunately, most lack a proper microenvironment producing poor mechanical properties and inaccurate extra-cellular matrix composition and organization. In this report we focused on mechanical properties, extra-cellular matrix organization and cell interactions in human skin samples reconstructed with pure collagen or dermal decellularized extra-cellular matrices (S-dECM) and compared them to native human skin. We found that Full-thickness S-dECM samples presented stiffness two times higher than collagen gel and similar to ex vivo human skin, and proved for the first time that keratinocytes also impact dermal mechanical properties. This was correlated with larger fibers in S-dECM matrices compared to collagen samples and with a differential expression of F-actin, vinculin and tenascin C between S-dECM and collagen samples. This is clear proof of the microenvironment's impact on cell behaviors and mechanical properties. STATEMENT OF SIGNIFICANCE: In vitro skin models have been used for a long time for clinical applications or in vitro knowledge and evaluation studies. However, most lack a proper microenvironment producing a poor combination of mechanical properties and appropriate biological outcomes, partly due to inaccurate extra-cellular matrix (ECM) composition and organization. This can lead to limited predictivity and weakness of skin substitutes after grafting. This study shows, for the first time, the importance of a complex and rich microenvironment on cell behaviors, matrix macro- and micro-organization and mechanical properties. The increased composition and organization complexity of dermal skin decellularized extra-cellular matrix populated with differentiated cells produces in vitro skin models closer to native human skin physiology.

Impacto del aislamiento social por el COVID-19 en la calidad del sueño en adultos de 18 a 60 años en la República Dominicana: estudio observacional / Impact of social isolation due to COVID-19 on sleep quality in adults aged 18 to 60 years in the Dominican Republic: An observational study

Introducción: durante la actual situación de confinamiento surgida por el COVID-19, la población ha estado expuesta a estados emocionales donde su calidad de sueño se ha visto afectada. Por esta razón, esta investigación se ha propuesto determinar el impacto del aislamiento social por el COVID-19 en la calidad del sueño en adultos de 18 a 60 años en la República Dominicana. Materiales y métodos: este estudio observacional de corte transversal fue realizado en la República Dominicana en el 2020, específicamente en adultos de 18 a 60 años. La encuesta fue esparcida virtualmente vía Google Forms. Las variables utilizadas fueron categóricas (sexo, estado civil, zona de residencia, nivel académico, consumo de sustancias) y continuas (edad, calidad de sueño, nivel de estrés). De igual forma, se utilizaron encuestas aprobadas internacionalmente, como el Índice de Calidad de Sueño de Pittsburgh. Resultados: la población del estudio consistió en 821 participantes (edad media 30.94 años, 74.3 % mujeres). La prevalencia de una mala calidad del sueño fue de 80.7 %. La puntuación media del PSQI fue de 8.56 ± 4.20. Por otro lado, se destacó la relación del estrés con una mala calidad de sueño, obteniendo una p=0.00. Los factores independientes relacionados con la mala calidad del sueño incluyeron la edad y el sexo femenino. Conclusiones: el presente estudio muestra una visión general de las diferentes causas relacionadas a alteraciones en la calidad de sueño. Cabe destacar, la exposición a altos niveles de estrés durante el aislamiento social fruto de la pandemia causada por el COVID-19, asociado con una pobre calidad de sueño. Además, el sexo femenino mostró mayor tendencia a presentar trastornos de sueño, por igual los consumidores de alcohol.

Effect of Ionic Strength, Nanoparticle Surface Charge Density, and Template Diameter on Self-Limiting Single-Particle Placement: A Numerical Study.

For the bottom-up approach where functional materials are constructed out of nanoscale building blocks (e.g., nanoparticles), it is essential to have methods that are capable of placing the individual nanoscale building blocks onto exact substrate positions on a large scale and on a large area. One of the promising placement methods is the self-limiting single-particle placement (SPP), in which a single nanoparticle in a colloidal solution is electrostatically guided by electrostatic templates and exactly one single nanoparticle is placed on each target position in a self-limiting way. This paper presents a numerical study on SPP, where the effects of three key parameters, (1) ionic strength (IS), (2) nanoparticle surface charge density (σNP), and (3) circular template diameter (d), on SPP are investigated. For 40 different parameter sets of (IS, σNP, d), a 30 nm nanoparticle positioned at R⃗ above the substrate was modeled in two configurations (i) without and (ii) with the presence of a 30 nm nanoparticle at the center of a circular template. For each parameter set and each configuration, the electrostatic potentials were calculated by numerically solving the Poisson-Boltzmann equation, from which interaction forces and interaction free energies were subsequently calculated. These have identified realms of parameter sets that enable a successful SPP. A few exemplary parameter sets include (IS, σNP, d) = (0.5 mM, -1.5 µC/cm2, 100 nm), (0.05 mM, -0.5 µC/cm2, 100 nm), (0.5 mM, -1.5 µC/cm2, 150 nm), and (0.05 mM, -0.8 µC/cm2, 150 nm). This study provides clear guidance toward experimental realizations of large-scale and large-area SPPs, which could lead to bottom-up fabrications of novel electronic, photonic, plasmonic, and spintronic devices and sensors.

Utilizing the Four Tenets of Osteopathic Medicine as an intersectional framework for approaching sexual orientation and gender identity disclosure as a provider.

The Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and other (LGBTQI+) community continues to experience health inequity and unmet needs. This manuscript examines the application of the Four Tenets of Osteopathic Medicine (FTOM) during a patient's self-disclosure of their sexual orientation and/or gender identity to the provider, also known as coming out. Tenet One discusses the interplay between intersectionality and coming out. Tenet Two elucidates how coming out moves toward a balance of homeostasis and self-healing. Tenet Three examines how structure and function can be understood on a personal level and how society influences coming out. Tenet Four explains the resources available to facilitate the previously forementioned changes. By applying the Four Tenets, the provider may more readily understand what "coming out" means on personal and social levels and what implications they may have on their patients' health.