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Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once‐daily (test) and twice‐daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24 mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7 days. Plasma concentrations were collected on Days 4‐6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α‐dihydrotetrabenazine (α‐HTBZ) and β‐dihydrotetrabenazine (β‐HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration‐time curve over 24 hours at steady state (AUC0‐24 h,ss) and for maximum plasma concentrations at steady state (Cmax,ss). The GMRs for AUC0‐24 h,sswere 115% for deutetrabenazine and 95% for deuterated total (α+β)‐HTBZ; and the GMR for Cmax,ssfor deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ssof the active metabolites; the GMR was 78% for total (α+β)‐HTBZ. At steady state, deutetrabenazine administered as the once‐daily formulation was bioequivalent to the twice‐daily formulation for both AUC and Cmax,and the active metabolites were bioequivalent with regard to AUC0‐24 h,ss.

The use of machine learning (ML) algorithms has an environmental impact to be fully considered. This article presents a green-in-driven approach to the development of ML models. The aim thereof is to meet operational requirements while ensuring a suitable tradeoff between performance/reliability and energy consumption.

Most approaches to 3D printing at various scales are layer based, meaning they start with a 3D CAD model that is sliced into planar print paths to be translated to machine code. However, this approach entails a number of drawbacks, such as slow printing speeds, limited build volumes, allowable geometric properties, and material diversity. To overcome these limitations, the authors have developed a novel additive manufacturing process called Non-Planar Granular Printing (NGP). Compared to its layer-based counterpart, NGP enables non-planar 3D printing by selectively binding reusable granular particles to create free-form structures. In doing so, NGP leverages traditional powder-based additive manufacturing processes. However, instead of enclosing the extruded compounds within a three-axis layer-based system, NPG combines multi-axis robotic deposition capabilities with customizable build volume parameters, which drastically improves print speed, scalability and material versatility. The result is a process whose main advantage is to enable the rapid production of support-free and complex geometric forms using a wide range of materials in granular form. This paper introduces and analyzes a series of benchmark experiments conducted to demonstrate the practical workflow, general output capabilities, and volume-material limitations of the system. The research also lays a foundation of non-planar 3D extrusion that enables material transitions for functional gradience capabilities.

Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α‐dihydrotetrabenazine [α‐HTBZ] and β‐dihydrotetrabenazine [β‐HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration‐QTc (C‐QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12‐lead ECGs extracted from continuous ECG recordings. C‐QTc analysis, using linear mixed‐effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α‐HTBZ and β‐HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C‐QTc model with deuterated α‐HTBZ and β‐HTBZ was selected to best describe the C‐QTc relationship in pooled EM and PM data. This model predicted a placebo‐corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac‐related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

Multisystem inflammatory syndrome in children (MIS-C) is a novel disease that was identified during the COVID-19 pandemic and is characterised by systemic inflammation following SARS-CoV-2 infection. Early detection of MIS-C is a challenge given its clinical similarities to Kawasaki disease and other acute febrile childhood illnesses. We aimed to develop and validate an artificial intelligence algorithm that can distinguish among MIS-C, Kawasaki disease, and other similar febrile illnesses and aid in the diagnosis of patients in the emergency department and acute care setting.

The extent of capillary nonperfusion measure in seven fields ETDRS and widefield angiography follows a near-perfect, linear correlation in patients with CRVO. The average amount of nonperfusion in total retina exceeds by over three-fold the amount measured on seven fields.

Aim: We present the case of a 72-year-old male with advanced choroideremia and a left chronic rhegmatogenous retinal detachment, which to our knowledge is the first formal report of a retinal detachment in this disease.Background: Choroideremia is a rare X-linked inherited retinal dystrophy, caused by mutations in the CHMgene which encodes Rab escort protein 1 (REP1), and affected males typically experience a progressive centripetal loss of vision. The disease pathology is caused by a primary retinal pigment epithelium degeneration, which leads to secondary loss of photoreceptors and choriocapillaris. This in turn leads to fusion of the degenerate outer retinal layers resulting in a retinopexy that is known to make subretinal gene therapy particularly challenging in these patients.Conclusion: Although retinal gene therapy is commonly targeted to the macular area in choroideremia, the observation of a rhegmatogenous retinal detachment indicates that the peripheral retina may not fuse with the residual choroid as occurs in the equatorial and macular regions. If this hypothesis is correct, targeting gene therapy to the retinal periphery even in advanced cases may be feasible and could potentially be used to preserve navigational vision.

Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice.

Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT.

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following single‐dose administration, the mean concentration‐time profiles for the 2 treatment groups (autoinjector, n = 106; and prefilled syringe, n = 110) were similar. The point estimates for the back‐transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration–time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration–time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half‐life was approximately 29 days. Treatment‐related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment‐emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy‐to‐use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy.

We present a detailed three-dimensional (3D) view of a prominence eruption, coronal loop expansion, and coronal mass ejections (CMEs) associated with an M4.4 flare that occurred on 2011 March 8 in the active region NOAA 11165. Full-disk Hα images of the flare and filament ejection were successfully obtained by the Flare Monitoring Telescope (FMT) following its relocation to Ica University, Peru. Multiwavelength observation around the Hα line enabled us to derive the 3D velocity field of the Hα prominence eruption. Features in extreme ultraviolet were also obtained by the Atmospheric Imager Assembly onboard the Solar Dynamic Observatory and the Extreme Ultraviolet Imager on board the Solar Terrestrial Relations Observatory - Ahead satellite. We found that, following collision of the erupted filament with the coronal magnetic field, some coronal loops began to expand, leading to the growth of a clear CME. We also discuss the succeeding activities of CME driven by multiple interactions between the expanding loops and the surrounding coronal magnetic field.

ABSTRACTObjectivesIn TRANSFORM, de novokidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3–8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15.MethodsPatients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19.ResultsThe safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20.ConclusionThe immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21.CT.gov identifierNCT01950819.

A pesar de las advertencias de numerosas asociaciones profesionales, las benzodiacepinas (BZD) y los hipnóticos Z (Z) son ampliamente prescritos a los ancianos ya que son especialmente susceptibles de padecer insomnio y ansiedad, pero a su vez resultan especialmente sensibles a la aparición de efectos secundarios a dichos medicamentos. En este estudio evaluamos la prescripción de BZD/Z en una muestra de ancianos (≥65) que se presentan en el servicio de urgencias de un hospital por haber sufrido una caída.

Background. Cytokine storm syndromes (CSS) are life-threatening systemic inflammatory disorders caused by immune system dysregulation. They can lead to organ failure and are triggered by various factors, including infections, malignancy, inborn errors of immunity, and autoimmune conditions. Trisomy 21 (TS21), also known as Down syndrome, is a genetic disorder associated with immune dysfunction, increased infection susceptibility, and inflammation. While TS21 has been linked to infectious-triggered hyperinflammation, its role as a primary cause of CSS has not been confirmed. Case Presentation. We present a case of a 16-year-old male with TS21 with fever, rash, joint pain, and abdominal symptoms. Extensive investigations ruled out infections, autoimmune conditions, malignancies, and inborn errors of immunity as triggers for a CSS. The patient’s symptoms improved with treatment using IL-1 inhibition and corticosteroids. Conclusions. This case reinforces that TS21 is an immune dysregulation disorder and highlights the importance of considering CSS in TS21 patients, even when triggers are unclear. The positive response to IL-1 inhibition in this patient suggests that dysregulation of the IL-1 superfamily and the NLRP3 inflammasome may contribute to CSS in TS21. This finding raises the possibility of using IL-1 inhibition as a treatment approach for CSS in TS21 patients.

Carfilzomib (CFZ) is a second-generation proteasome inhibitor used to treat multiple myeloma. Potent inhibition of the proteasome results in chronic proteotoxic endoplasmic reticulum (ER) stress, leading to apoptosis. While CFZ has improved survival rates in multiple myeloma, it is associated with an increased risk of cardiovascular adverse effects. While this has been putatively linked to cardiotoxicity, CFZ could potentially also exhibit adverse effects on the endothelium.

Inherited retinal disease (IRD) is a leading cause of blindness. Recent advances in gene-directed therapies highlight the importance of understanding the genetic basis of these disorders. This study details the molecular spectrum in a large United Kingdom (UK) IRD patient cohort.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P =.006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R− high-risk group (P< .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819.

TRANSFORM(TRANSplant eFficacy and safety Outcomes with an eveRolimus‐based regiMen) was a 24‐month, prospective, open‐label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced‐exposure calcineurin inhibitor (EVR+ rCNI) or mycophenolate with standard‐exposure CNI. Consistent with previously reported 12‐month findings, noninferiority of the EVR+ rCNIregimen for the primary endpoint of treated biopsy‐proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = −0.3, 8.7; P = .006). Mean eGFRwas stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2) in both arms. The incidence of de novo donor‐specific antibodies (dnDSA) was lower in the EVR+ rCNIarm (12.3% vs 17.6%) among on‐treatment patients. Although discontinuation rates due to adverse events were higher with EVR+ rCNI(27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BKvirus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR+ rCNIeven in the D+/R− high‐risk group (P <.0001). In conclusion, the EVR+ rCNIregimen offers comparable efficacy and graft function with low tBPARand dnDSArates and significantly lower incidence of viral infections relative to standard‐of‐care up to 24 months. Clinicaltrials.gov number: NCT01950819. Two‐year follow‐up findings from TRANSFORM, the largest study in de novo renal transplantation to date, demonstrate that everolimus‐facilitated calcineurin inhibitor reduction provides a valid alternative to standard‐of‐care immunosuppression comprising mycophenolate with standard calcineurin inhibitor by offering comparable antirejection efficacy, stable renal function, and significant benefit in protecting from viral infections.

ABSTRACTIntroduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels.Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed.Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.

Assessing risk for QTc interval prolongation in a thorough QTc study is a standard recommendation when evaluating new chemical entities. As part of the clinical development program for odanacatib, an oral selective inhibitor of cathepsin K previously in development for the treatment of osteoporosis, 2 clinical studies in healthy subjects assessed pharmacokinetics and overall safety (including potential for delayed ventricular repolarization) of a supratherapeutic dose. In study 1, subjects received a supratherapeutic dose regimen of odanacatib (300 mg on day 1, then daily multiple doses of 25 mg to day 21) or placebo. In study 2 (days 1–4), subjects received the odanacatib supratherapeutic dose regimen or moxifloxacin (positive control, single 400‐mg dose on day 4; matching placebo for odanacatib/moxifloxacin) or placebo. All doses were administered with a high‐fat meal. In study 1 (N = 12), the supratherapeutic dosing regimen achieved exposure ∼3.5‐fold of the proposed therapeutic dose (50 mg once weekly) and was sufficiently well tolerated to permit assessment in the thorough QTc study (study 2). In study 2 (N = 116), the primary objective was placebo‐corrected change from baseline in QTcF interval (Fridericia's correction), assessed by replicate electrocardiograms (12‐lead Holter recordings; days –1 through 7). Supratherapeutic odanacatib dosing was not associated with increased risk of prolonged QT interval, unlike moxifloxacin (confirming assay sensitivity). Pooled safety data across both studies suggested that the safety profile of odanacatib at high exposures was similar to placebo, with a small clustering of oral cavity adverse events. Odanacatib was not associated with increased risk of prolonged QT interval.

Background Undocumented undergraduates are a growing population in the United States. Despite being shut out from many resources, such as access to federal financial aid and social services, many are thriving by contributing to their families and communities. Few studies to date have taken a strengths-based approach to understand the lives of undocumented young adults or examined their normative developmental experiences.Purpose The purpose of this study was to examine how contribution manifests in the lives of Latino undocumented undergraduates and the extent to which they are engaged in and contribute to their families and communities.Research Design This study employed a convergent mixed-methods design in which parallel quantitative and quantitative data were collected and analyzed separately. Through mixed methods, this article examines the family and community responsibilities of a sample of N = 797 Latino undocumented undergraduate student survey respondents, along with three portraits of qualitative visual and verbal narratives.Results Results highlight the value of “collective contribution” in Latino undocumented immigrant families. Through quantitative methods, results reveal that the majority of Latino undocumented undergraduates are contributing to their families and communities in significant ways. Qualitative findings reveal ways in which cultural values manifest as the reciprocal contribution between individuals and their families and communities. Further, results reveal the varied ways that Latino undocumented undergraduates engage with their families and communities, exhibiting the characteristics of ideal citizens, despite being denied a pathway to citizenship.Conclusions The results suggest that Latino undocumented college students are thriving and contributing to the society that gives them conflicting messages about how to belong. Yet, they enter postsecondary institutions and continue to remain engaged in their families and communities. Their engagement has important implications for what type of society we will become and for the need to build on these social resources to make our democracy and community stronger, recognizing immigrants as a resource to strengthen the social fabric of our society.

Inadequate cytotoxicity testing accepted by European Union (EU) and International Organization for Standardization (ISO) standards for perfluoro-octane used in intraocular surgery resulted in 117 cases of acute intraocular toxicity and severe loss of visual function. Clinical findings and an alternative method to determine cytotoxicity are described.

Malnutrition (MN) is a common entity in patients with liver cirrhosis (LC) and has a negative impact on mortality. This study aimed to describe the prevalence of MN through subjective global assessment (SGA) and anthropometry in patients with LC and to analyze its relationship with the severity of the disease.