Successful quality improvement project to increase hydroxyurea prescriptions for children with sickle cell anaemia.

Hydroxyurea (HU) is an effective but underused disease-modifying therapy for patients with sickle cell anaemia (SCA). EMBRACE SCD, a sickle cell disease treatment demonstration project, aimed to improve access to HU by increasing prescription (Rx) rates by at least 10% from baseline in children with SCA.The Model for Improvement was used as the quality improvement framework. HU Rx was assessed from clinical databases in three paediatric haematology centres. Children aged 9 months-18 years with SCA not on chronic transfusions were eligible for HU treatment. The health belief model was the conceptual framework to discuss with patients and promote HU acceptance. A visual aid showing erythrocytes under the effect of HU and the American Society of Hematology HU brochure were used as educational tools. At least 6 months after offering HU, a Barrier Assessment Questionnaire was given to assess reasons for HU acceptance and refusals. If HU was declined, the providers discussed with family again. We conducted chart audits to find missed opportunities to prescribe HU as one plan-do-study-act cycle.At initial measurement, 50.2% of 524 eligible patients had HU prescribed. During the testing and initial implementation phase, the mean performance after 10 data points was 53%. After 2 years, the mean performance was 59%, achieving an 11% increase in mean performance and a 29% increase from initial to the last measurement (64.8% HU Rx). During a 15-month period, 32.1% (N=168) of the eligible patients who were offered HU completed the barrier questionnaire with 19% (N=32) refusing HU, mostly based on not perceiving enough severity of their children's SCA or fearing side effects.Reviewing patient charts for missed opportunity of offering HU with feedback and evaluating the reasons of declining HU via a questionnaire were key components in increasing HU Rx in our population.

Safety and efficacy of methylprednisolone versus dexamethasone in critically ill patients with COVID-19 acute respiratory distress syndrome: a retrospective study.

Background: Corticosteroids (CSs), specifically dexamethasone (DEX), are the treatment of choice for severe acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia (CARDS). However, data from both ARDS and relatively small CARDS clinical trials have suggested improved outcomes with methylprednisolone (MP) versus DEX. The objective of this retrospective cohort study was to compare the safety and effectiveness of MP and DEX in critically ill CARDS patients. Methods: The study cohort included CARDS patients admitted to a tertiary referral intensive care unit (ICU) between April and September 2020 who received at least 5 days of CSs for CARDS. Results: The cohort was notable for a high severity of illness (overall, 88.5% of patients required mechanical ventilation and 16% required vasopressors on admission). The DEX group (n = 62) was significantly older with a higher illness severity [Sequential Organ Failure Assessment (SOFA) 6 (4.75-8) versus 4.5 (3-7), p = 0.008], while the MP group (n = 51) received significantly more loading doses [19 (37.3%) versus 4 (6.5%), p < 0.0001]. MP was associated with a shorter time to intubation and more rapid progression to mortality [days to death: 18 (15-23) versus 27 (15-34), p = 0.026]. After correction for baseline imbalances in age and SOFA score, DEX was associated with improved mortality at 90 days compared with MP [hazard ratio (HR) = 0.43, 95% confidence interval (CI) = 0.23-0.80, p = 0.008]. However, there were no differences between rates of secondary infections during hospitalization or insulin requirements at 7 and 14 days. Conclusion: In this cohort of critically ill CARDS, choice of CS was associated with mortality but not adverse event profile, and thus warrants further investigation.

Comparison of Amantadine, Modafinil, and Standard of Care in the Acute Treatment of Disorders of Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Many patients who experience severe TBI have persistent disorders of consciousness. Amantadine and modafinil are used for some neurological disorders; however, a comparison of the 2 medications in TBI has not been reported. This study compared the effectiveness of amantadine, modafinil, and standard of care (SOC) on disorders of consciousness after TBI. METHODS: All adult TBI patients admitted between January 1, 2017, and September 31, 2020 who received amantadine, modafinil, or SOC treatments were screened. Data collection included: demographics, change in Glasgow Coma Scale (GCS), location of hemorrhage, medication duration, intensive care unit and hospital length of stay, adverse drug reactions, and concomitant sedative medications. Patients in the amantadine and modafinil groups were matched 1:2 with patients who received SOC therapies. The primary outcome was change in GCS ≥ 3 from baseline to discharge. RESULTS: A total of 142 patients met inclusion criteria. Medications were initiated a median of 8 days from admission. Patients in the SOC group experienced a greater improvement in GCS and shorter hospital length of stay compared with amantadine. A change in GCS ≥ 3 from medication initiation to hospital discharge occurred in 46.5% of amantadine patients and 53.8% of modafinil patients. CONCLUSIONS: In this study, TBI patients did not benefit from amantadine or modafinil compared with SOC therapies, and no differences were found between medication groups. Further studies are warranted to determine whether the addition of amantadine or modafinil in the weeks after TBI provides benefit.

Correlates of bird collisions with buildings across three North American countries.

Collisions with buildings cause up to 1 billion bird fatalities annually in the United States and Canada. However, efforts to reduce collisions would benefit from studies conducted at large spatial scales across multiple study sites with standardized methods and consideration of species- and life-history-related variation and correlates of collisions. We addressed these research needs through coordinated collection of data on bird collisions with buildings at sites in the United States (35), Canada (3), and Mexico (2). We collected all carcasses and identified species. After removing records for unidentified carcasses, species lacking distribution-wide population estimates, and species with distributions overlapping fewer than 10 sites, we retained 269 carcasses of 64 species for analysis. We estimated collision vulnerability for 40 bird species with ≥2 fatalities based on their North American population abundance, distribution overlap in study sites, and sampling effort. Of 10 species we identified as most vulnerable to collisions, some have been identified previously (e.g., Black-throated Blue Warbler [Setophaga caerulescens]), whereas others emerged for the first time (e.g., White-breasted Nuthatch [Sitta carolinensis]), possibly because we used a more standardized sampling approach than past studies. Building size and glass area were positively associated with number of collisions for 5 of 8 species with enough observations to analyze independently. Vegetation around buildings influenced collisions for only 1 of those 8 species (Swainson's Thrush [Catharus ustulatus]). Life history predicted collisions; numbers of collisions were greatest for migratory, insectivorous, and woodland-inhabiting species. Our results provide new insight into the species most vulnerable to building collisions, making them potentially in greatest need of conservation attention to reduce collisions and into species- and life-history-related variation and correlates of building collisions, information that can help refine collision management.

Correlaciones de las Colisiones de Aves contra Edificios en Tres Países de América del Norte Resumen Las colisiones contra los edificios causan hasta mil millones de fatalidades de aves al año en los Estados Unidos y en Canadá. Sin embargo, los esfuerzos por reducir estas colisiones se beneficiarían con estudios realizados a grandes escalas espaciales en varios sitios de estudio con métodos estandarizados y considerando las variaciones relacionadas a la historia de vida y a la especie y las correlaciones de las colisiones. Abordamos estas necesidades de investigación por medio de una recolección coordinada de datos sobre las colisiones de aves contra edificios en los Estados Unidos (35), Canadá (3) y México (2). Recolectamos todos los cadáveres y los identificamos hasta especie. Después de retirar los registros de cadáveres no identificados, las especies sin estimaciones poblacionales a nivel distribución y las especies con distribuciones traslapadas en menos de diez sitios, nos quedamos con 269 cadáveres de 64 especies para el análisis. Estimamos la vulnerabilidad a colisiones para 40 especies con ≥2 fatalidades con base en la abundancia poblacional para América del Norte, el traslape de su distribución entre los sitios de estudio y el esfuerzo de muestreo. De las diez especies que identificamos como las más vulnerables a las colisiones, algunas han sido identificadas previamente (Setophaga caerulescens), y otras aparecieron por primera vez (Sitta carolinensis), posiblemente debido a que usamos una estrategia de muestreo más estandarizada que en los estudios previos. El tamaño del edificio y el área del vidrio estuvieron asociados positivamente con el número de colisiones para cinco de ocho especies con suficientes observaciones para ser analizadas independientemente. La vegetación alrededor de los edificios influyó sobre las colisiones solamente para una de esas ocho especies Catharus ustulatus). Las historias de vida pronosticaron las colisiones; el número de colisiones fue mayor para las especies migratorias, insectívoras y aquellas que habitan en las zonas boscosas. Nuestros resultados proporcionan una nueva perspectiva hacia las especies más vulnerables a las colisiones contra edificios, lo que las pone en una necesidad potencialmente mayor de atención conservacionista para reducir estas colisiones y de estudio de las variaciones relacionadas con la especie y la historia de vida y las correlaciones de las colisiones contra edificios, información que puede ayudar a refinar el manejo de colisiones.

Modified gaphene oxide (GO) particles in peptide hydrogels: a hybrid system enabling scheduled delivery of synergistic combinations of chemotherapeutics.

The scheduled delivery of synergistic drug combinations is increasingly recognized as highly effective against advanced solid tumors. Of particular interest are composite systems that release a sequence of drugs with defined kinetics and molar ratios to enhance therapeutic effect, while minimizing the dose to patients. In this work, we developed a homogeneous composite comprising modified graphene oxide (GO) nanoparticles embedded in a Max8 peptide hydrogel, which provides controlled kinetics and molar ratios of release of doxorubicin (DOX) and gemcitabine (GEM). First, modified GO nanoparticles (tGO) were designed to afford high DOX loading and sustained release (18.9% over 72 h and 31.4% over 4 weeks). Molecular dynamics simulations were utilized to model the mechanism of DOX loading as a function of surface modification. In parallel, a Max8 hydrogel was developed to release GEM with faster kinetics and achieve a 10-fold molar ratio to DOX. The selected DOX/tGO nanoparticles were suspended in a GEM/Max8 hydrogel matrix, and the resulting composite was tested against a triple negative breast cancer cell line, MDA-MB-231. Notably, the composite formulation afforded a combination index of 0.093 ± 0.001, indicating a much stronger synergism compared to the DOX-GEM combination co-administered in solution (CI = 0.396 ± 0.034).

Regulation of myosin heavy chain antisense long noncoding RNA in human vastus lateralis in response to exercise training.

Alterations to muscle activity or loading state can induce changes in expression of myosin heavy chain (MHC). For example, sedentary individuals that initiate exercise training can induce a pronounced shift from IIx to IIa MHC. We sought to examine the regulatory response of MHC RNA in human subjects in response to exercise training. In particular, we examined how natural antisense RNA transcripts (NATs) are regulated throughout the MHC gene locus that includes MYH2 (IIa), MYH1 (IIx), MYH4 (IIb), and MYH8 (Neonatal) in vastus lateralis before and after a 5-wk training regime that consisted of a combination of aerobic and resistance types of exercise. The exercise program induced a IIx to IIa MHC shift that was associated with a corresponding increase in transcription on the antisense strand of the IIx MHC gene and a decrease in antisense transcription of the IIa MHC gene, suggesting an inhibitory mechanism mediated by NATs. We also report that the absence of expression of IIb MHC in human limb muscle is associated with the abundant expression of antisense transcript overlapping the IIb MHC coding gene, which is the opposite expression pattern as compared with that previously observed in rats. The NAT provides a possible regulatory mechanism for the suppressed expression of IIb MHC in humans. These data indicate that NATs may play a regulatory role with regard to the coordinated shifts in MHC gene expression that occur in human muscle in response to exercise training.

Tuning Contact Line Dynamics and Deposition Patterns in Volatile Liquid Mixtures.

The spreading of a pure, volatile liquid on a wettable substrate has been studied in extensive detail. Here we show that the addition of a miscible, nonvolatile liquid can strongly alter the contact line dynamics and the final liquid deposition pattern. We observe two distinct regimes of behavior depending on the relative strength of solutal Marangoni forces and surface wetting. Fingerlike instabilities precede the deposition of a submicron thick film for large Marangoni forces and small solute contact angles, whereas isolated pearl-like drops emerge and are deposited in quasicrystalline patterns for small Marangoni forces and large solute contact angles. This behavior can be tuned by directly varying the contact angle of the solute liquid on the solid substrate.

Use of Intraventricular Medications in Critically Ill Patients: A Systematic Review.

New evidence and increased use of intracranial devices have increased the frequency of intraventricular (IVT) medication administration in the neurologic intensive care unit. Significant benefits and risks are associated with administration of medications directly into the central nervous system. This review summarizes important literature, along with key information for clinicians regarding the administration, dosing, monitoring, and adverse effects related to IVT medication usage. Multiple medications have supporting literature for their use in critically ill patients including amphotericin B, aminoglycosides, colistimethate, daptomycin, quinupristin/dalfopristin, vancomycin, alteplase, and nicardipine. Sterile preparation and delivery, along with different types of devices that support medication administration, are also reviewed. One randomized, placebo-controlled trial of alteplase demonstrated decreased mortality but no change in good functional outcome. Other reports of IVT medication use are mainly limited to case reports and retrospective case series. There is a need for increased research on the topic; however, several practical barriers decrease the likelihood of a large, placebo-controlled, prospective study for most indications. Providers should consider implementing protocols to maximize safety of IVT medication delivery to ensure optimal patient outcomes.

Hunting and mountain sheep: Do current harvest practices affect horn growth?

The influence of human harvest on evolution of secondary sexual characteristics has implications for sustainable management of wildlife populations. The phenotypic consequences of selectively removing males with large horns or antlers from ungulate populations have been a topic of heightened concern in recent years. Harvest can affect size of horn-like structures in two ways: (a) shifting age structure toward younger age classes, which can reduce the mean size of horn-like structures, or (b) selecting against genes that produce large, fast-growing males. We evaluated effects of age, climatic and forage conditions, and metrics of harvest on horn size and growth of mountain sheep (Ovis canadensis ssp.) in 72 hunt areas across North America from 1981 to 2016. In 50% of hunt areas, changes in mean horn size during the study period were related to changes in age structure of harvested sheep. Environmental conditions explained directional changes in horn growth in 28% of hunt areas, 7% of which did not exhibit change before accounting for effects of the environment. After accounting for age and environment, horn size of mountain sheep was stable or increasing in the majority (~78%) of hunt areas. Age-specific horn size declined in 44% of hunt areas where harvest was regulated solely by morphological criteria, which supports the notion that harvest practices that are simultaneously selective and intensive might lead to changes in horn growth. Nevertheless, phenotypic consequences are not a foregone conclusion in the face of selective harvest; over half of the hunt areas with highly selective and intensive harvest did not exhibit age-specific declines in horn size. Our results demonstrate that while harvest regimes are an important consideration, horn growth of harvested male mountain sheep has remained largely stable, indicating that changes in horn growth patterns are an unlikely consequence of harvest across most of North America.

Precursors to Molecular Slip on Smooth Hydrophobic Surfaces.

Experiments and simulations suggest that simple liquids may experience slip while flowing near a smooth, hydrophobic surface. Here we show how precursors to molecular slip can be observed in the complex response of a liquid to oscillatory shear. We measure both the change in frequency and bandwidth of a quartz crystal microbalance during the growth of a single drop of water immersed in an ambient liquid. By varying the hydrophobicity of the surface using self-assembled monolayers, our results show little or no slip for water on all surfaces. However, we observe excess transverse motion near hydrophobic surfaces due to weak binding in the corrugated surface potential, an essential precursor to slip. We also show how this effect can be easily missed in simulations utilizing finite-ranged interaction potentials.

Stroke in a Child with Hemoglobin SC Disease: A Case Report Describing use of Hydroxyurea after Transfusion Therapy.

Children with hemoglobin SC (HbSC) disease suffer a significant incidence of silent cerebral infarcts but stroke is rare. A 2-year-old African American boy with HbSC disease presented with focal neurologic deficits associated with magnetic resonance imaging evidence of cerebral infarction with vascular abnormalities. After the acute episode he was treated with monthly transfusions and subsequently transitioned to hydroxyurea therapy. The benefits of hydroxyurea as a fetal hemoglobin inducer in HbSC disease, to ameliorate clinical symptoms are supported by retrospective studies. This case highlights the rare occurrence of stroke in a child with HbSC disease and the use of hydroxyurea therapy.

On Making Statistical Inferences Regarding the Relationship between Spawners and Recruits and the Irresolute Case of Western Atlantic Bluefin Tuna (Thunnus thynnus).

Forecasts of the future abundance of western Atlantic bluefin tuna (Thunnus thynnus) have, for nearly two decades, been based on two competing views of future recruitment potential: (1) a "low" recruitment scenario based on hockey-stick (two-line) curve where the expected level of recruitment is set equal to the geometric mean of the recruitment estimates for the years after a supposed regime-shift in 1975, and (2) a "high" recruitment scenario based on a Beverton-Holt curve fit to the time series of spawner-recruit pairs beginning in 1970. Several investigators inferred the relative plausibility of these two scenarios based on measures of their ability to fit estimates of spawning biomass and recruitment derived from stock assessment outputs. Typically, these comparisons have assumed the assessment estimates of spawning biomass are known without error. It is shown here that ignoring error in the spawning biomass estimates can predispose model-choice approaches to favor the regime-shift hypothesis over the Beverton-Holt curve with higher recruitment potential. When the variance of the observation error approaches that which is typically estimated for assessment outputs, the same model-choice approaches tend to favor the single Beverton-Holt curve. For this and other reasons, it is argued that standard model-choice approaches are insufficient to make the case for a regime shift in the recruitment dynamics of western Atlantic bluefin tuna. A more fruitful course of action may be to move away from the current high/low recruitment dichotomy and focus instead on adopting biological reference points and management procedures that are robust to these and other sources of uncertainty.

Immunogenicity of pneumococcal vaccination in a patient with sickle hemoglobinopathy: a case report.

Despite decrease in morbidity and mortality from invasive pneumococcal disease (IPD), individuals with asplenia remain at risk for IPD compared to the general population. This report describes a young adult with hemoglobin SD and documented splenic autoinfarction with pneumococcal sepsis, meningitis, and pneumonia within seven months of immunization with PPSV-23.

Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.

Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/ß-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2(+)/PAX6(+) neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains.

Pharmacotherapeutic strategies for patients treated for depression in UK primary care: a database analysis.

OBJECTIVE: To investigate long-term patterns of antidepressant treatment in patients in primary care in the UK, and to assess their healthcare resource use and disease outcomes. RESEARCH DESIGN AND METHODS: A retrospective longitudinal cohort study was conducted using the Clinical Practice Research Datalink. The study population comprised patients aged ≥18 years with depression receiving a prescription for antidepressant monotherapy between 1 January 2006 and 31 December 2011 with no antidepressants within the preceding 6 months. Recovery was defined by timing of antidepressant prescriptions (≥6 months without treatment). Treatment lines and strategies (switching, combining, augmenting and resuming medication) were analyzed. Healthcare resource use for the different treatment strategies and periods of no therapy was assessed. RESULTS: Data from 123,662 patients (287,564 treatment lines) were analyzed. Switching and resumption of treatment were more frequent than other strategies. Recovery was highest with first-line monotherapy (45% of patients), while as a second-line strategy switching was more successful (43%) than combination or augmentation. In subsequent lines of treatment, switching was associated with successively lower rates of recovery (31% in the third line and 24% from the fourth line onwards). Similar rates were observed for resumption. Healthcare resource use was greater during antidepressant use than treatment-free periods. Augmentation was associated with the highest proportions of patients with a psychiatrist referral, psychologist referral and psychiatric hospitalization. CONCLUSIONS: This study provides extensive real-world information on the prescribing patterns and treatment outcomes for a large cohort of patients treated for depression with antidepressants in primary care. Switching is more frequently used than augmentation or combination treatment, with decreasing effectiveness across successive lines. Key limitations of the study were: (i) risk of selection bias due to the use of inclusion criteria based on depression diagnoses recorded by the practitioner; and (ii) reliance on prescribing patterns as proxies for clinical outcomes, such as recovery.

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs.

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Two essential peritrophic matrix proteins mediate matrix barrier functions in the insect midgut.

The peritrophic matrix (PM) in the midgut of insects consists primarily of chitin and proteins and is thought to support digestion and provide protection from abrasive food particles and enteric pathogens. We examined the physiological roles of 11 putative peritrophic matrix protein (PMP) genes of the red flour beetle, Tribolium castaneum (TcPMPs). TcPMP genes are differentially expressed along the length of the midgut epithelium of feeding larvae. RNAi of individual PMP genes revealed no abnormal developmental phenotypes for 9 of the 11 TcPMPs. However, RNAi for two PMP genes, TcPMP3 and TcPMP5-B, resulted in depletion of the fat body, growth arrest, molting defects and mortality. In situ permeability assays after oral administration of different-sized FITC-dextran beads demonstrated that the exclusion size of the larval peritrophic matrix (PM) decreases progressively from >2 MDa to <4 kDa from the anterior to the most posterior regions of the midgut. In the median midguts of control larvae, 2 MDa dextrans were completely retained within the PM lumen, whereas after RNAi for TcPMP3 and TcPMP5-B, these dextrans penetrated the epithelium of the median midgut, indicating loss of structural integrity and barrier function of the larval PM. In contrast, RNAi for TcPMP5-B, but not RNAi for TcPMP3, resulted in breakdown of impermeability to 4 and 40 kDa dextrans in the PM of the posterior midgut. These results suggest that specific PMPs are involved in the regulation of PM permeability, and that a gradient of barrier function is essential for survival and fat body maintenance.