Search

Purpose: Alpelisib is a PI3K (Phosphoinositide 3-kinases) inhibitor used for breast cancer which develops hyperglycemia based on its action on glucose metabolism regulation. This study aims to identify potential risk factors predicting hyperglycemia development and the need for multiple treatments for hyperglycemia in patients receiving Alpelisib. Methods: Fourteen women diagnosed with metastatic hormone receptor-positive breast cancer carrying PI3K mutations who initiated treatment with Alpelisib were monitored through consultations in the Oncology and Endocrinology departments. Non-parametric ROC curves were generated to assess the need for three or more antidiabetic medications to achieve glycemic control. Results: The study population had a median age of 64 years (range:48–69) with a median body mass index (BMI) of 26.6 kg/m2(range: 22.9–29.4). Overweight was observed in 35.7% of the participants and obesity in 21.4%. Fifty percent of the participants had prediabetes, and 85.7% developed hyperglycemia requiring pharmacological treatment, although none of them needed to discontinue treatment for this reason. Baseline C-peptide levels and BMI were associated with the number of antidiabetic drugs used (Spearman’s Rho 0.553, p = 0.040; Spearman’s Rho 0.581, p = 0.030, respectively). ROC curve analysis showed and area under the curve (AUC) of 0.819 for the variable risk profile (defined as baseline C-peptide >10.5 ng/ml and BMI > 27 kg/m2), whereas AUC values were 0.556 and 0.514 for HbA1c and baseline glucose, respectively, (p = 0.012). Conclusion: A joint follow-up by an Oncology department and a Diabetes Unit can prevent treatment discontinuation in patients under Alpelisib therapy. Baseline BMI and plasma C-peptide levels can predict an increased need for anti-hyperglycemic treatment.

Cis-regulatory elements (CREs) control gene expression, orchestrating tissue identity, developmental timing and stimulus responses, which collectively define the thousands of unique cell types in the body1–3. While there is great potential for strategically incorporating CREs in therapeutic or biotechnology applications that require tissue specificity, there is no guarantee that an optimal CRE for these intended purposes has arisen naturally. Here we present a platform to engineer and validate synthetic CREs capable of driving gene expression with programmed cell-type specificity. We take advantage of innovations in deep neural network modelling of CRE activity across three cell types, efficient in silico optimization and massively parallel reporter assays to design and empirically test thousands of CREs4–8. Through large-scale in vitro validation, we show that synthetic sequences are more effective at driving cell-type-specific expression in three cell lines compared with natural sequences from the human genome and achieve specificity in analogous tissues when tested in vivo. Synthetic sequences exhibit distinct motif vocabulary associated with activity in the on-target cell type and a simultaneous reduction in the activity of off-target cells. Together, we provide a generalizable framework to prospectively engineer CREs from massively parallel reporter assay models and demonstrate the required literacy to write fit-for-purpose regulatory code.

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET–DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

Interventions supporting parents of young children often target parenting or parental mental health separately. Multi-component parenting and parental mental health interventions have the potential to improve parenting practices, mental health, and early childhood development. We aimed to examine their impact on child and parent outcomes.

Saugeye (Sauger Sander canadensis× Walleye S. vitreus) have been introduced in reservoirs for several purposes, including as a top‐down control to combat stunting in crappie Pomoxisspp. populations. However, no comprehensive diet evaluation has been completed in southern reservoirs. Our objectives were to assess variability in saugeye diet compositions, explore factors influencing crappie presence in saugeye diets, and investigate trends in prey size to inform management strategies regarding predatory control of crappie populations. We collected 2638 saugeye diets from six Oklahoma reservoirs. We used permutational multivariate analysis of variance to test differences in diet compositions among saugeye lengths, study reservoirs, and seasons, and we used logistic regression models to correlate the presence of crappie in diets with saugeye size, season, crappie abundance, productivity, and turbidity. Finally, we used bivariate plots of diet indices and quantile regression to explore trends in prey importance and prey size relative to saugeye size. Saugeye diet compositions were best explained by saugeye size, followed by study reservoir and season. Saugeye exhibited an ontogenetic shift from Inland Silverside Menidia beryllinato shad Dorosomaspp., and crappie were eaten infrequently in comparison. The presence of crappie prey in diets was most correlated with saugeye size (primarily large saugeye), followed by higher crappie abundance, lower reservoir productivity, and season (highest in fall). Saugeye consumed larger prey than most piscivores relative to predator size. Our results indicated that dominant prey of saugeye transitioned from smaller‐bodied fishes to larger shad as they grew when both prey types were available, which may have implications for growth and recruitment. Ultimately, the low and variable use of crappie prey may lead to inconsistent predatory effects on crappie populations, and large saugeye may exert greater top‐down pressure on crappie in lakes with lower productivity or higher crappie abundance. Impact statementDominant prey type of saugeye in Oklahoma reservoirs transitioned from Inland Silverside to Gizzard Shad as they grew, and crappie were eaten infrequently in comparison. Large saugeye may exert greater top‐down pressure on crappie populations in lakes with lower productivity or higher crappie abundance. Dominant prey type of saugeye in Oklahoma reservoirs transitioned from Inland Silverside to Gizzard Shad as they grew, and crappie were eaten infrequently in comparison. Large saugeye may exert greater top‐down pressure on crappie populations in lakes with lower productivity or higher crappie abundance.

La tirotoxicosis representa el estado clínico secundario al exceso de hormonas tiroideas (HT). Puede originarse tanto por un aumento de la síntesis y liberación de HT por parte de la glándula tiroides (hipertiroidismo, causa más frecuente), como por inflamación y destrucción tiroidea, producción ectópica o administración exógena de HT. El diagnóstico es bioquímico y se basa en la determinación de la hormona estimulante del tiroides (TSH) y de las hormonas tiroideas (tiroxina y triyodotironina). Para planificar un tratamiento eficaz resulta crucial identificar la causa subyacente, siendo la enfermedad de Graves-Basedow la más común, seguida por el bocio multinodular tóxico y el adenoma tiroideo tóxico. Menos frecuentes, aunque relevantes, son las tiroiditis, la producción extratiroidea de HT y la tirotoxicosis facticia. Algunas pruebas de imagen, como la ecografía-Doppler y la gammagrafía tiroidea, son de ayuda en el diagnóstico etiológico. El objetivo del tratamiento es lograr el control sintomático y reducir la síntesis y secreción de HT mediante el uso de fármacos o tratamientos radicales (radioyodo o cirugía).

Las pruebas analíticas son cruciales para el cribado, el diagnóstico, el tratamiento y el seguimiento de la patología tiroidea. A día de hoy, no se recomienda el cribado universal de la función tiroidea, indicándose su determinación en función de los síntomas y situaciones específicas del paciente. La medición aislada de TSH (tirotropina) se considera en la actualidad el estándar de cribado, indicándose la determinación a posterioride las cifras de T4 libre y T3 según el resultado. Así mismo, la determinación de anticuerpos es fundamental para el diagnóstico de la disfunción tiroidea autoinmune. Errores comunes en la interpretación incluyen la presencia de enfermedad no tiroidea, interferencias en los inmunoensayos o algunos fármacos. Este protocolo ofrece una guía práctica para interpretar y aplicar pruebas en la patología tiroidea, destacando consideraciones clave en el diagnóstico.

El nódulo tiroideo consiste en el crecimiento de una lesión tiroidea que se delimita y distingue del parénquima tiroideo normal. Su incidencia está incrementándose debido al aumento de pruebas de imagen (incidentalomas tiroideos), sin que ello repercuta en una mejora en la supervivencia del cáncer de tiroides. Se ha de realizar una evaluación de la función tiroidea con medición de hormona estimulante del tiroides (TSH), comprobando así la funcionalidad del nódulo. Además, siempre se ha de efectuar una aproximación inicial de la probabilidad de malignidad mediante ecografía tiroidea que categorice cada nódulo según el Sistema Europeo de Informes e Imágenes de Tiroides (EU-TIRADS), indicando el riesgo de malignidad y, asimismo, el tamaño con el que debemos realizar una citología tiroidea (mediante punción aspiración con aguja fina). La citología nos permitirá clasificar los nódulos según las categorías Bethesda que nos aportará una estimación del riesgo de malignidad, lo cual será de suma importancia para decidir el manejo (observación frente a cirugía).

El hipotiroidismo es una de las patologías endocrinológicas más prevalentes en la práctica clínica habitual. La etiología más frecuente a nivel mundial es el déficit de yodo, y en países con ingesta suficiente de yodo es la tiroiditis de Hashimoto. En este sentido, es importante realizar una adecuada anamnesis y exploración física de cara a su diagnóstico, aunque la confirmación viene determinada por el análisis bioquímico. El protocolo de cribado universal consiste en la medición inicial de las cifras de TSH y en caso de alteración las de T4L. Los límites de normalidad de la TSH son controvertidos, continúan siendo objeto de debate a día de hoy y presentan condicionantes asociados como son la gestación o el límite de la normalidad en la población anciana. El tratamiento sustitutivo no siempre está indicado y cuando lo está es de elección la levotiroxina oral.

This article examines the validity of a newly developed research instrument, the Customers' Experience of Banking e-Services (CEBES) scale. The study was conducted in Saudi Arabia during the COVID‐19 pandemic; it used both exploratory and confirmatory factor analysis to measure the original 75-item scale. A convenience sampling technique was used to select 555 electronic banking services customers. Exploratory factor analysis yielded a four-factor, 54-item scale, which was run with a cutoff point of .5 to ensure high proportional contribution of each scale item. The four factors were: reflections on bank processing of complaints; recovery of e-banking services; bank webpages; and perceived safety and confidentiality of information. The newly developed scale could be used to measure customers' experience of banking e-service and identify areas requiring improvement. Despite achieving an acceptable level of statistical strength, the 54-item CEBES requires further testing on other populations.

Raynaud-Claes syndrome is rare condition characterized with intellectual disability and is caused by X-linked pathogenic variants in CLCN4gene. Hemizygous missense variant NM_001830.4: c.1597G>A (p.V533M) was detected in a 6-year-old male followed up with intellectual disability, dysmorphism, and epileptic encephalopathy. The mother and one sister of the patient were also carrying the same variant. The clinical picture of the patient was significantly more severe, and the patient exhibited nonconvulsive status. Tonic status was observed with benzodiazepine treatment and the patient was successfully treated with a ketogenic diet. Many types of seizures can be seen in Raynaud-Claes syndrome, some of which can be life-threatening. CLCN4variants can be investigated in patients who exhibit an increase in tonic seizures with benzodiazepine treatment. However, ketogenic dietary therapy as first-line treatment can be lifesaving in resistant epilepsy cases caused by the CLCN4gene.

Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 β-arrestin recruitment-based high-throughput screening campaign, we identified urea 19as a hit with a LPAR1 IC50value of 5.0 μM. Hit-to-lead activities revealed that one of the urea nitrogen atoms can be replaced by carbon and establish the corresponding phenylacetic amide as a lead structure for further optimization. Medicinal chemistry efforts led to the discovery of piperidine 18as a potent and selective LPAR1 antagonist with oral activity in a mouse model of LPA-induced skin vascular leakage. The molecular scaffold of 18shares no obvious structural similarity with any other LPAR1 antagonist disclosed so far.

ABSTRACTThis scoping review aims to map and summarize practice-based research that evaluates outcomes in teaching and learning about the Holocaust (TLH). It focuses on providing an overview of the characteristics of existing literature and synthesizing the educational interventions’ effects evaluated in previous studies. Nineteen bibliographical databases were searched for relevant empirical research published from 1945 to 2020 worldwide. After screening and relevance assessment, 117 research publications were identified for inclusion in the review. The included material was analysed by bibliometric analysis, thematic analysis of educational approaches, and narrative synthesis of outcomes. Based on the bibliometric analysis, the findings suggest that practice-based research on TLH’s educational outcomes is a neglected subfield within the academic field of TLH, with a lack of cumulative development across studies. The scoping review also showed a dominance of studies conducted with qualitative study designs. The narrative synthesis of outcomes showed that these studies provide important insights into how interventions within TLH impact students; nonetheless, these studies need to be supplemented with knowledge from quantitative studies. Without such knowledge, we have a knowledge gap that could imply that TLH interventions are implemented arbitrarily, that students do not learn the intended lessons, or that the lessons are not lasting.

Mixed-integer optimal control problems arise in many practical applications combining nonlinear, dynamic, and combinatorial features. To cope with the resulting complexity, several approaches have been suggested in the past. Some of them rely on solving a reformulated and relaxed control problem, referred to as partial outer convexification (POC). Inspired by an efficient algorithm for switching time optimization by Stellato and coworkers, SwitchTimeOpt.jl, we developed an algorithmic approach for POC implemented in a Julia package. Both approaches are based on linearization and exponential integration to obtain second derivatives. We show the efficiency and applicability of the novel approach by comparing it to SwitchTimeOpt.jl, by extending the concept and calculations to the treatment of constraints, and by investigating warm starting of switching time optimization. An additional comparison to a CasADi-based standard single shooting approach shows a significant reduction in computational time despite an increase in iterations. The new solver facilitates the reliable and fast solution of mixed-integer optimal control problems.

In backscatter communication (BC), a passive tag transmits information by just affecting an external electromagnetic field through load modulation. Thereby, the feed current of the excited tag antenna is modulated by adapting the passive termination load. This paper studies the achievable information rates with a freely adaptable passive load. As a prerequisite, we unify monostatic, bistatic, and ambient BC with circuit-based system modeling. We present the crucial insight that channel capacity is described by existing results on peak-power-limited quadrature Gaussian channels, because the steady-state tag current phasor lies on a disk. Consequently, we derive the channel capacity for the case of an unmodulated external field, for general passive, purely reactive, or purely resistive tag loads. We find that modulating both resistance and reactance is important for very high rates. We discuss the capacity-achieving load statistics, rate asymptotics, technical conclusions, and rate losses from value-range-constrained loads (which are found to be small for moderate constraints). We then demonstrate that near-capacity rates can be attained by more practical schemes: 1) amplitude-and-phase-shift keying on the reflection coefficient and 2) simple load circuits of a few switched resistors and capacitors. Finally, we draw conclusions for the ambient BC channel capacity in important special cases.

The ENCODE Consortium’s efforts to annotate noncoding cis-regulatory elements (CREs) have advanced our understanding of gene regulatory landscapes. Pooled, noncoding CRISPR screens offer a systematic approach to investigate cis-regulatory mechanisms. The ENCODE4 Functional Characterization Centers conducted 108 screens in human cell lines, comprising >540,000 perturbations across 24.85 megabases of the genome. Using 332 functionally confirmed CRE–gene links in K562 cells, we established guidelines for screening endogenous noncoding elements with CRISPR interference (CRISPRi), including accurate detection of CREs that exhibit variable, often low, transcriptional effects. Benchmarking five screen analysis tools, we find that CASA produces the most conservative CRE calls and is robust to artifacts of low-specificity single guide RNAs. We uncover a subtle DNA strand bias for CRISPRi in transcribed regions with implications for screen design and analysis. Together, we provide an accessible data resource, predesigned single guide RNAs for targeting 3,275,697 ENCODE SCREEN candidate CREs with CRISPRi and screening guidelines to accelerate functional characterization of the noncoding genome.

Introduction:Pathogenic variants in several genes encoding components of the mitochondrial respiratory chain have been linked to various clinical phenotypes such as progressive cavitating leukoencephalopathy (PCL). The association between PCL, previously linked to numerous gene mutations in the literature, and the NDUFV2gene mutations has emerged as a recent and noteworthy discovery. PCL is generally diagnosed in symptomatic patients during the early years of life, mostly in infancy. Case Presentation:In a previously healthy 12-year-old Turkish girl, a computed tomography scan taken for minor head trauma incidentally revealed suspicious hypodense areas in the periventricular white matter. Subsequently, a magnetic resonance imaging evaluation was performed. There was no history of motor regression, irritability, or seizures up to the age of 12. The case exhibited normal neurological and cranial nerve examinations. Magnetic resonance imaging detected bilateral periventricular T2/FLAIR hyperintensities with cystic areas suggestive of PCL. Whole-exome sequencing revealed the presence of a homozygous p.R222C missense variant in the NDUFV2gene. Over a 6-year follow-up period, the patient remained asymptomatic, and there were no discernible changes in the magnetic resonance imaging findings. Conclusion:This case underscores the association between a potentially causal variant at the NDUFV2locus and PCL. It is worth noting that this novel variation in PCL can not only manifest with symptoms in the infantile period but also remain asymptomatic into adolescence.

Shatsky Rise is a large oceanic plateau formed at a spreading ridge triple junction, but its origin mechanism is unclear. Voluminous magmatism at Shatsky Rise has been regarded either as the product of decompression melting of fertile recycled material in a divergent plate boundary setting (plate model) or a hot mantle plume head (plume model). Here we use thermodynamic models to simulate decompression melting of heterogeneous mantle sources. We provide constraints on both mantle potential temperature and fertile source abundance under seafloor spreading and plume–ridge interaction scenarios. As constrained by crustal thickness and lava chemical compositions, a seafloor spreading origin requires mantle potential temperatures of 1,490–1,585 °C, which are unreasonably high for mid-ocean ridge systems far from hotspots. In contrast, the plume–ridge interaction model can explain observations with mantle potential temperatures of 1,470–1,515 °C for the buoyant plume and upwelling rates up to six times the rate of plate separation during the formation of the main massifs. Fertile recycled material comprises less than 7% of the mantle source, and predicted melt fractions are consistent with independent estimates. We thus suggest that Shatsky Rise magmatism is best explained by plume–ridge interaction—a combination of the plume and plate models.

Purpose: This paper aims to explore the epistemic connections between three instructional coaches and a first-year in-service teacher during remote planning and debrief meetings. Prior evidence suggests that remote instructional coaching leads to better teaching practices and identifies the instructional coaching moves used to prompt teacher reflection. Design/methodology/approach: In this study, the authors utilized quantitative ethnography and epistemic network analysis (ENA) approaches to explore the epistemic frames of three remote university-based instructional coaches as they supported a first-year in-service teacher. Findings: Quantitative ENA findings shed light on the network connections between instructional coaches and teachers, as well as the epistemic frames observed during planning and debrief meetings. Additionally, the authors provide qualitative findings that complement and reinforce the quantitative results. Research limitations/implications: All data collection occurred via Zoom, and the class was in a hybrid modality, with some students attending class in person and some attending remotely via Zoom. This unique context could have impacted the epistemic connections surrounding technology and logistics. Practical implications: This study provides a practical codebook for use in future studies that explores instructional coaching. Findings from this study can be used to inform instructional coaching decisions. Originality/value: The ENA findings helped deepen the authors' understanding of how instructional coaches can support a first-year in-service teacher during planning and debrief meetings in several ways. Additionally, this study presents a unique context given the COVID-19 pandemic and the remote model of instructional coaching.

Survivin, a well-known member of the inhibitor of apoptosis protein family, is upregulated in many cancer cells, which is associated with resistance to chemotherapy. To circumvent this, inhibitors are currently being developed to interfere with the nuclear export of survivin by targeting its protein–protein interaction (PPI) with the export receptor CRM1. Here, we combine for the first time a supramolecular tweezer motif, sequence-defined macromolecular scaffolds, and ultrasmall Au nanoparticles (us-AuNPs) to tailor a high avidity inhibitor targeting the survivin-CRM1 interaction. A series of biophysical and biochemical experiments, including surface plasmon resonance measurements and their multivalent evaluation by EVILFIT, reveal that for divalent macromolecular constructs with increasing linker distance, the longest linkers show superior affinity, slower dissociation, as well as more efficient PPI inhibition. As a drawback, these macromolecular tweezer conjugates do not enter cells, a critical feature for potential applications. The problem is solved by immobilizing the tweezer conjugates onto us-AuNPs, which enables efficient transport into HeLa cells. On the nanoparticles, the tweezer valency rises from 2 to 16 and produces a 100-fold avidity increase. The hierarchical combination of different scaffolds and controlled multivalent presentation of supramolecular binders was the key to the development of highly efficient survivin-CRM1 competitors. This concept may also be useful for other PPIs.

Nurses play an essential role in managing mental health conditions, such as posttraumatic stress disorder (PTSD), especially in rural areas where access to mental health care is limited. Posttraumatic stress disorder may emerge at the end of life and complicate health care and is a particular concern for aging Vietnam veterans. We describe the development of 3 videos that illustrate how to recognize PTSD, respond to trauma disclosures, and manage PTSD in cognitive impairment during an in-home hospice nurse visit. Through problem identification and needs assessment, we identified 6 goals and 28 specific content objectives presented through cinematic action with flashbacks or voice-over narration with graphics. Videos were evaluated through a survey (N = 155) and analysis of “chat” responses (N = 186) to targeted questions during a webinar presentation to clinicians (N = 345). Approximately 75% rated videos as “very much” relevant to needs, having helped learn something new, and realistic. Analysis of chat responses showed videos conveyed most content objectives (92%). In addition, participants stated videos were helpful in demonstrating nursing skills of listening, responding, and displaying empathy, as well as showing case presentations involving cognitive impairment and the patient experience. Participants expressed a desire for longer videos/more information including a wider range of PTSD presentations and comorbidities.

A theoretical investigation is presented to study the orbital angular momentum (OAM) beam scattering from a topological insulator (TI) cylinder coated with metamaterials. To calculate the electromagnetic (EM) response of the scattered field, the field equations are modified using Laguerre–Gaussian (LG) potential and plane wave scattering. The response of the metamaterial coated geometry has been reported for Double positive (DPS), Double negative (DNG), Epsilon negative (ENG), and Mu negative (MNG) coating layers, respectively. The normalized bistatic echo widths for the TI cylinder also change by changing the topological charge (l), the radius of the metamaterial coated layer (b), source frequency (f), and beam waist radius (w0). Our result for LG00beam exactly tones with plane wave scattering as a reference. Numerical results in the form of bistatic echo widths have been calculated. Besides, the prementioned parameters, the influence of OAM mode index on the bistatic echo width is also analyzed. It can be seen that OAM mode number plays major role in controlling the scattering amplitude and intensity.

Quantum computers may demonstrate significant advantages over classical devices, as they are able to exploit a purely quantum-mechanical phenomenon known as entanglement in which a single quantum state simultaneously populates two-or-more classical configurations. However, due to environmental noise and device errors, elaborate quantum entanglement can be difficult to prepare on modern quantum computers. In this paper, we introduce a metric based on the condensation of qubits to assess the ability of a quantum device to simulate many-electron systems. Qubit condensation occurs when the qubits on a quantum computer condense into a single, highly correlated particle-hole state. While conventional metrics like gate errors and quantum volume do not directly target entanglement, the qubit-condensation metric measures the quantum computer’s ability to generate an entangled state that achieves nonclassical long-range order across the device. To demonstrate, we prepare qubit condensations on various quantum devices and probe the degree to which qubit condensation is realized via postmeasurement analysis. We show that the predicted ranking of the quantum devices is consistent with the errors obtained from molecular simulations of H2using a contracted quantum eigensolver.

Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min.

Regulators attest that energy efficiency standards save consumers money. More efficient light bulbs, appliances, and vehicles would cost more up front but reduce energy expenses by enough to compensate. Using data on American drivers and cars, we show this to be true, but only on average. Many drivers could save money in less fuel-efficient cars. In fact, we find little correlation between mileage and fuel economy. A driver’s income, sex, age, and education are far more closely associated with their vehicle’s fuel economy. Rich drivers are not more sensitive to fuel costs, undermining claims that borrowing constraints explain the mismatch.

This qualitative study documents and analyzes COVID-19’s impacts on burn care in twelve nations. Burn care saw valuable improvements in surgical techniques, skin grafting, and other acute treatments during the decades before the COVID-19 pandemic which increased severely burned patients’ survival rates and quality of life. Detailed interviews, conducted in the 12 nations reveal that the COVID-19 pandemic greatly affected the delivery of acute and rehabilitation services for burn patients. Resources have been suctioned away from non-COVID healthcare and burn care has not been spared. Acute, post-acute rehabilitation, and mental health services have all suffered. Weak preparation has deeply burdened health care services in most nations, resulting in lower access to care. Access problems have accelerated innovations like telehealth in many nations. The spread of misinformation through social and traditional media has contributed to the varied responses to COVID-19. This compounded problems in health care delivery. Burn care providers delivered services for survivors during extremely difficult circumstances by continuing to furnish acute and long-term services for patients with complex disease. Emphasis on future pandemic preparedness will be vital because they undermine all aspects of burn care and patient outcomes. As the COVID-19 pandemic continues to unfold around the world, it will be important to continue to monitor and analyze the adaptability of nations, health care systems, and burn care providers.

Warburg micro syndrome (WARBM) is a rare, autosomal recessive, neurodevelopmental disorder characterized by microcephaly, cortical dysplasia, corpus callosum hypoplasia, congenital hypotonia leading to subsequent spastic quadriplegia, severe developmental delay and hypogenitalism. Ophthalmologic findings that may affect any ocular segment including characteristic, small, atonic pupils. WARBM is known to be caused by biallelic, pathogenic variants in at least five genes although additional genetic loci may exist. The RAB3GAP1c.748 + 1G>A, p.Asp250CysfsTer24 founder variant has been described in families of Turkish ancestry. We report the clinical and molecular findings in three, unrelated, Turkish families with WARBM. A novel c.974−2A>G variant causing WARBM in three siblings of Turkish descent was found. Functional studies of the novel, c.2606 + 1G>A variant in patients’ mRNA revealed skipping of exon 22 which results in a premature stop codon in exon 23. However, the clinical consequences of this variant are blended given that the individual also had a maternally inherited chromosome 3q29 microduplication.

Thirty-five years ago, Joseph Carens published “Aliens and Citizens: The Case for Open Borders” in the Review of Politics. It is only a slight overstatement to say that this article created the subfield of political theory of migration. Today, the field is flourishing. Migration continues to be one of today's most politically fraught and morally urgent issues. An estimated hundred million people have fled violence and persecution. Hundreds of millions more cross international borders every year. States have responded with highly restrictive policies, in which people need to resort to perilous routes, often in the hands of smugglers, to claim asylum.

Hailed as a major reform, the No Surprises Act (NSA) is a profoundly conservative law that aims neither to reform design of insurance, to regulate fees, nor to limit health care spending. The NSA mitigates a perverse but narrow problem: unpredictable and uncontrollable high out-of-pocket bills for individuals who are unable to receive care within their insurance network. However, the NSA neglects to address the broader high medical costs, limited choice of caregivers, and the resulting insecurity and unfairness that characterize American health care. It allows caregivers to extract high payments and insurers to restrict choice of caregivers. Insurers can continue to employ ineffective cost controls that generate unpredictable high out-of-pocket costs for patients—and high levels of denial of payments to doctors and hospitals. The law amputated the most politically and visibly gangrenous consequences of unregulated private insurance in the United States in ways that enable business as usual in private health insurance to persist, subject to unnecessarily complex arbitration rules that magnify administrative waste.

ObjectivePulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance–compliance (RC) time, the product of PAC and pulmonary vascular resistance, is reported to be a physiological constant. We investigated if differences in PAC and RC time exist between pulmonary hypertension (PH) subgroups and examined whether PAC is an independent predictor of transplant-free survival in PAH.MethodsThis was a retrospective analysis of adult PAH (n=532) and chronic thromboembolic PH (CTEPH, n=84) patients enrolled in the US Pulmonary Hypertension Association Registry from 2015 to 2019. PAC and RC time were compared between PH subgroups (connective tissue disease-PAH (CTD-PAH), idiopathic/heritable-PAH (i/h-PAH), drug/toxin-PAH (d/t-PAH)). Cox proportional hazards models were constructed for transplant-free survival, adjusting for REVEAL 2.0 risk score.ResultsThere were no differences in estimated PAC between PAH subgroups, nor between PAH and CTEPH. RC time was shorter in CTEPH compared with PAH (median 0.55 (IQR 0.45–0.64) vs 0.62 (0.52–0.73) s, p<0.0001). RC time was shortest in CTD-PAH when compared with i/h-PAH and d/t-PAH ((0.59±0.18) vs (0.65±0.20) vs (0.73±0.25) s, p=0.0001). PAC was associated with transplant-free survival (HR 0.72, 95% CI 0.55 to 0.94, p=0.02) but was not an independent predictor of outcome after adjustment for REVEAL 2.0 score.ConclusionPAC was similar between PH groups and was not an independent predictor of transplant-free survival in PAH. RC time was different between PH subgroups, challenging RC time constancy.Trial registration numberNCT04071327

Agent-based simulations, especially those including communication, are complex to model and execute. To help researchers deal with this complexity and to encourage modular and maintainable research software, the Python-based framework mango(modular python agent framework) has been developed. The framework enables users to quickly implement software agents with different communication protocols and message codecs. Furthermore, mangoprovides various options for developing an integrated agent simulation. This includes a scheduler module, which can control the agents’ tasks, a (distributed) clock mechanism for time synchronization, and a specific simulation component, which can be coupled with other (co-)simulation software. These features are complemented by modular implementation patterns and a well-evaluated performance with the ability to simulate across multiple computing processes to ensure scalability.

Objective To evaluate retinal nerve fiber layer (RNFL) thickness, central macular thickness (CMT), and subfoveal choroid thickness (CT) by using optical coherence tomography (OCT) in adolescents with newly diagnosed epilepsy and patients who had been using Na valproate (VPA) for at least 1 year.Methods We examined 60 patients with genetic generalized epilepsy (GGE) aged 8–17 years. Thirty patients with newly diagnosed GGE who were evaluated before the beginning of the therapy and another 30 patients who were chosen from among adolescents with epilepsy using VPA for at least 1 year were included in the study.Results Nasal quadrant RNFL thickness and CMT measurements were significantly lower in the monotherapy group compared with the newly diagnosed group (p= 0.044 and p= 0.032, respectively). CT measurements were not significantly different between the groups (p= 0.413). There was a negative correlation in regression analysis between the duration of drug use and RNFL thickness in all quadrants.Conclusion According to our study, we observed thinning of the nasal RNFL and macular thickness in adolescents with epilepsy who were using Na valproate for at least 1 year and that as the duration of use increased, the thinning occurred in all RNFL quadrants. Further studies with larger series are needed to better understand the effects of both epilepsy and VPA on the eye.

An outstanding challenge in chemical computation is the many-electron problem where computational methodologies scale prohibitively with system size. The energy of any molecule can be expressed as a weighted sum of the energies of two-electron wave functions that are computable from only a two-electron calculation. Despite the physical elegance of this extended “aufbau” principle, the determination of the distribution of weights─geminal occupations─for general molecular systems has remained elusive. Here we introduce a new paradigm for electronic structure where approximate geminal-occupation distributions are “learned” via a convolutional neural network. We show that the neural network learns the N-representability conditions, constraints on the distribution for it to represent an N-electron system. By training on hydrocarbon isomers with only 2–7 carbon atoms, we are able to predict the energies for isomers of octane as well as hydrocarbons with 8–15 carbons. The present work demonstrates that machine learning can be used to reduce the many-electron problem to an effective two-electron problem, opening new opportunities for accurately predicting electronic structure.

AbstractThis paper determines optimal public debt in a life cycle model with incomplete markets that matches the empirically observed variation in consumption, labor, and savings. We find that public savings—not public debt—equal to 168 percent of output is optimal, primarily due to the influence of the life cycle on household decision-making. By inducing a lower interest rate, public savings slow consumption and leisure growth over an average household’s lifetime, and the resulting flatter allocation of lifetime consumption and leisure improves welfare. These life cycle welfare benefits are large—on net, they outweigh the transitional costs from a tax-financed public debt elimination. (JEL D15, D52, E21, E43, E62, G51, H63)

•Chronic graft-versus-host disease (cGVHD) is associated with nonmalignant late effects (NM-LEs) but not with subsequent neoplasms.•Severe cGVHD features are more closely associated with nonmalignant NM-LEs.•The duration of systemic immunosuppression was not predictive for LEs.

Se describe el caso de un paciente varón de 52años que consulta al servicio de reumatología por presentar adenopatías indoloras en las regiones cervical, axilar, supraclaviculares y en la nuca, así como fiebre, aumento de tamaño de parótidas y submaxilares. Se realizan estudios complementarios que arrojan como resultado anemia normocítica-normocrómica, trombocitopenia y eosinofilia, alteración de la función renal con hipoalbuminemia y hematuria, FAN 1/5.120, Sm+, ACL+ y biopsia de los tejidos comprometidos, por lo que se arriba al diagnóstico de enfermedad de Rosai-Dorfman y enfermedad relacionada con IgG4. Se discuten diagnósticos diferenciales de adenopatías cervicales, axilares e inguinales, fiebre, compromiso renal y hematológico.

While remarkable improvements have been made to acute hospital burn care in recent decades, it is not matched by improvements in post-acute care, including physical rehabilitation and mental health. Progress in acute hospital treatment of burn survivors now highlights the next important step—addressing care once a patient leaves intensive treatment and is discharged to the community. Long-term physical rehabilitation and mental health services are vital to improving quality of life for burn survivors. Using qualitative methods, we apply an adapted Reeve framework to assess and compare post-acute physical rehabilitation and mental health care across 13 countries on 6 continents. Twenty semistructured interviews were conducted with burn surgeons and rehabilitation specialists. One major theme that emerged was the importance of training and resources to the quality of post-acute care. This exploratory study suggests the value of investing scarce resources in a range of low-cost interventions to improve follow-up burn care. One intervention identified here is short-term training in post-acute rehabilitation and mental health to upgrade and standardize best clinical practices to address as-yet unmet post-discharge needs of burn survivors.