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Abstract Background Checkpoint inhibitor pneumonitis (CIP) that develops following immune checkpoint inhibitor (ICI) treatment can be difficult to distinguish from other common etiologies of lung inflammation in cancer patients. Here, we evaluate the bronchoalveolar lavage fluid (BAL) for potential biomarkers specific to CIP. Methods We conducted a retrospective study of patients who underwent standard of care bronchoscopy to compare the cytokines of interest between patients with and without CIP and with and without immune-mediated pulmonary diseases. Pulmonary diagnoses were determined by the treating clinician at the time of bronchoscopy and retroactively reviewed for agreement by the study team. Results Thirty-seven patients were included, and 24 (64.9%) had pulmonary infection, 2 (5.4%) had pulmonary edema, 6 (16.2%) had non-CIP drug-induced pneumonitis, 3 (8.1%) had CIP, 5 (13.5%) had immune-mediated ILD or autoimmune vasculitis, 4 (10.8%) had cancer progression, and 4 (10.8%) had nonimmune-mediated interstitial lung disease (ILD). IL-6 from the BAL was significantly higher in patients with CIP compared to those with cancer progression and nonimmune-mediated ILD, and IL-6 was significantly higher in patients with immune-mediated pulmonary diseases compared to cancer progression, nonimmune-mediated ILD, and infection. Conclusions BAL IL-6 distinguished CIP from other common, important causes of pulmonary infiltrates in patients with cancer, suggesting it may give insight into the pathophysiology of CIP and has potential as a biomarker.

Abstract Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. Mechanistically, LTCC inhibition by RRAD or nifedipine induced CM cell cycle by modulating calcineurin activity. Moreover, ectopic expression of RRAD/CDK4/CCND in combination induced CM proliferation in vitro and in vivo, improved cardiac function and reduced scar size post-myocardial infarction.

Background:. Healthcare professionals in plastic and reconstructive surgery (PRS) face unique stressors that contribute to burnout, increasing the risk of errors and compromising patient care. Despite this, there is limited research on PRS burnout in the United States. This study aimed to measure burnout rates and identify high-impact improvement targets within a PRS division at a US academic medical center. Methods:. A sequential mixed-methods study was conducted, involving systems analysis and contextual design methods. All surgeons (n = 5) and nonsurgeons (n = 9) were invited to participate (total n = 14). Burnout rates were measured, and workplace stressors were identified using surveys, focus groups, and contextual inquiries. High-impact, low-effort improvement targets were determined through impact-effort matrices. Results:. Survey data from 13 respondents revealed an 85% burnout rate. Three focus groups and 14 contextual inquiries were conducted. After 13 participants validated and prioritized 2 affinity diagrams and provided 24 high-priority stressors, 8 respondents completed 2 surveys that yielded 6 high-impact/low-effort targets for organizational improvement efforts. Conclusions:. This study highlights the high prevalence of burnout in PRS and identifies specific improvement targets for both surgeons and nonsurgeons. Findings suggest strategies such as improving respect and recognition for surgeons and streamlining clinic flow for nonsurgeons. Implementing these targeted improvements can enhance the well-being of healthcare professionals and ultimately improve patient care. The study’s methods can be replicated by other healthcare organizations to identify and address burnout-related issues effectively.

Background: Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model. Results: Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact. Conclusions: These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on.

Objective The ADVOCATE trial demonstrated that treatment of active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with avacopan was noninferior in achieving remission at week 26 and superior for sustained remission at week 52 compared with a prednisone taper. This analysis of ADVOCATE evaluated the efficacy and safety of avacopan in patients with ear, nose, throat (ENT), or lung manifestations. Methods This post hoc analysis included patients enrolled in ADVOCATE with ENT or lung manifestations at baseline. Outcomes included remission at weeks 26 and 52, respiratory tract manifestations over time, relapse rate, glucocorticoid‐related toxicity, health‐related quality of life (HRQoL), and safety. Results ADVOCATE included 144 patients with ENT manifestations (avacopan: n = 75, prednisone taper: n = 69) and 142 with lung manifestations (avacopan: n = 71, prednisone taper: n = 71). Among patients with ENT manifestations, remission was achieved at week 26 by 72.0% (avacopan group) and 71.0% (prednisone taper group) and was sustained at week 52 by 62.7% (avacopan) and 53.6% (prednisone taper). Among patients with lung manifestations, remission was achieved at week 26 by 73.2% (avacopan) and 66.2% (prednisone taper) and sustained at week 52 by 67.6% (avacopan) and 53.5% (prednisone taper). The relapse rate, glucocorticoid toxicity, and measures of HRQoL favored avacopan for both respiratory tract manifestation groups. Safety was comparable across treatment groups. Conclusion Patients with GPA or MPA with ENT or lung manifestations demonstrated similar responses to avacopan, reflecting results reported in the overall ADVOCATE trial population and supporting the administration of avacopan in these subgroups.

Background: The Fontan operation is associated with chronic venous hypertension, liver and renal disease, and several other sequelae. The alterative surgical approach, when feasible, a biventricular conversion (BiV), may diminish some of these long-term risks. Objectives: The aim of this study was to compare long-term outcomes of patients undergoing BiV with those undergoing a destination Fontan operation. Methods: We identified all patients with univentricular physiology cared for at Boston Children’s Hospital between 2007 and 2022 and divided them into those who received BiV or Fontan operations. Outcomes included 10-year incidences of modified major adverse cardiovascular events (MACE), liver dysfunction, renal dysfunction, and transplant-free survival. Outcomes in the 2 groups were compared using propensity matching. Results: A total of 927 patients were evaluated, 341 BiV and 586 Fontan. Following propensity matching, 258 patients from each group were compared. There were no differences between groups in estimated 10-year freedom from MACE (P = 0.70), transplant-free survival (P = 0.70), or freedom from renal disease (P = 0.60). However, estimated 10-year freedom from liver disease was greater in BiV patients (82% BiV vs 71% Fontan, P = 0.02). Incidence rate per 100 person-years follow-up of surgical interventions and readmissions was higher among BiV patients (10.11 vs 1.85, P

Abstract The pan-immune-inflammation value (PIV), calculated as (neutrophil × platelet × monocyte)/lymphocyte count, may be useful for estimating survival in breast cancer patients. To determine the prognostic value of PIV for overall survival in breast cancer patients in Lima, Peru. A retrospective cohort study was conducted. 97 breast cancer patients diagnosed between January 2010 and December 2016 had their medical records analyzed. The primary dependent variable was overall survival, and the key independent variable was the PIV, divided into high (≥ 310) and low (

Several reports in education have called for transforming physics learning environments by promoting sensemaking of real-world scenarios in light of curricular ideas. Recent advancements in Generative-Artificial Intelligence have garnered increasing traction in educators' community by virtue of its potential to transform STEM learning. In this exploratory study, we adopt a mixed-methods approach in comparatively examining student- and AI-generated responses to two different formats of a physics problem through the theoretical lenses of sensemaking and mechanistic reasoning. The student data is derived from think-aloud interviews of introductory students and the AI data comes from ChatGPT's (versions 3.5 and 4o) solutions collected using Zero shot approach. The results highlight AI responses to evidence most features of the two processes through well-structured solutions and student responses to effectively leverage representations in their solutions through iterative refinement of arguments. In other words, while AI responses reflect how physics is talked about, the student responses reflect how physics is practiced. Implications of these results in light of development and deployment of AI systems in physics pedagogy are discussed.

Abstract Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14–3–3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14–3–3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14–3–3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14–3–3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14–3–3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14–3–3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Abstract Background To assess the outcome of previously untreated patients with perihilar cholangiocarcinoma who present to a cancer referral center with or without pre-existing trans-papillary biliary drainage. Methods Consecutive patients with a diagnosis of perihilar cholangiocarcinoma presenting between January 1, 2013, and December 31, 2017, were identified from a prospective surgical database and by a query of the institutional database. Of 237 patients identified, 106 met inclusion criteria and were reviewed. Clinical information was obtained from the Electronic Medical Record and imaging studies were reviewed in the Picture Archiving and Communication System. Results 73 of 106 patients (69%) presenting with a new diagnosis of perihilar cholangiocarcinoma underwent trans-papillary biliary drainage (65 endoscopic and 8 percutaneous) prior to presentation at our institution. 8 of the 73 patients with trans-papillary biliary drainage (11%) presented with and 5 developed cholangitis; all 13 (18%) required subsequent intervention; none of the patients without trans-papillary biliary drainage presented with or required drainage for cholangitis (p = 0.008). Requiring drainage for cholangitis was more likely to delay treatment (p = 0.012) and portended a poorer median overall survival (13.6 months, 95%CI [4.08, not reached)] vs. 20.6 months, 95%CI [18.34, 37.51] p = 0.043). Conclusion Trans-papillary biliary drainage for perihilar cholangiocarcinoma carries a risk of cholangitis and should be avoided when possible. Clinical and imaging findings of perihilar cholangiocarcinoma should prompt evaluation at a cancer referral center before any intervention. This would mitigate development of cholangitis necessitating additional drainage procedures, delaying treatment and potentially compromising survival.

Abstract Background Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. Results In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. Conclusions Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.

Introduction: In Peru, adherence to antihypertensive treatment ranges from 55.5% to 46.6%. Adherence decreases under adverse socioeconomic conditions. Objective: The aim of this research was to evaluate the socioeconomic inequalities in non-adherence to antihypertensive medication in Peru. Methods: A cross-sectional study was conducted through the analysis of data from the Demographic and Family Health Survey carried out in Peru between 2013 and 2023. We addressed the socioeconomic conditions of hypertensive Peruvian adults, including sex, age group, educational level, area or place of residence, and health insurance. These conditions were evaluated as sources of inequality in non-adherence to antihypertensive medication at a general level using the Concentration Index (CI) or Erreygers’ Concentration Index (ECI) among hypertensive adults over 29 years old. Results: In the 15,624 hypertensive adults older than 29 years included in the study, 86.63% were adherent to their antihypertensive medication. However, the inequality in medication non-adherence was considerable (CI: -0.259; 95%CI: -0.385 to -0.132; p

Abstract During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.

In the past decade, several species of platygastroid wasps were found to be adventive in North America and Europe while under evaluation in quarantine as biological control agents of invasive pests. The scope and relative risk of this phenomenon is not fully known, but it is clearly a trend with implications for classical biological control. As a means of assessing the issue and to provide a global baseline, we implemented a data-mining approach with DNA sequences in the Barcode of Life Database, yielding 201 platygastroid BINs with intercontinental and island distributions. At least fifty-five BINs displayed exact COI barcode matches across continents, with many more BINs scored as inconclusive due to sequence length variation. These intercontinental and island BINs include biocontrol agents known to be adventive, as well as many species identified only to genus with uncertain geographic origins. We provide 2,500 identifications for platygastroid BOLD BINs, 88% to genus, to encourage additional research on this distributional phenomenon. The intercontinental BOLD BINs were compared to literature records and GBIF occurrences of cosmopolitan species to identify gaps and discordance across data sources. Smaller COI barcode datasets from localities in Florida and Germany, including topotypical specimens, revealed more intercontinental matches. We analyzed COI sequences in BOLD for the entirety of Insecta and Araneae to assess this phenomenon more broadly and because these taxa contain many hosts for platygastroid wasps. This method revealed that the intercontinental distribution phenomenon is widespread with implications for assessing biological diversity, taxonomic methodology and regulatory frameworks.

The safety and efficacy of hepatic artery embolization (HAE) in treating intrahepatic cholangiocarcinoma (IHC) was evaluated. Initial treatment response, local tumor progression-free survival (L-PFS), and overall survival (OS) were evaluated in 34 IHC patients treated with HAE. A univariate survival analysis and a multivariate Cox proportional hazard analysis to identify independent factors were carried out. Objective response (OR) at 1-month was 79.4%. Median OS and L-PFS from the time of HAE was 13 (CI = 95%, 7.4–18.5) and 4 months (CI = 95%, 2.09–5.9), respectively. Tumor burden < 25% and increased tumor vascularity on preprocedure imaging and surgical resection prior to embolization were associated with longer OS (p < 0.05). Multivariate logistic regression analysis demonstrated that tumor burden < 25% and hypervascular tumors were independent risk factors. Mean post-HAE hospital stay was 4 days. Grade 3 complication rate was 8.5%. In heavily treated patients with IHC, after exhausting all chemotherapy and other locoregional options, HAE as a rescue treatment option appeared to be safe with a mean OS of 13 months. Tumor burden < 25%, increased target tumor vascularity on pre-procedure imaging, and OR on 1 month follow-up images were associated with better OS. Further studies with a control group are required to confirm the effectiveness of HAE in IHC.

Background Robust risk assessment is crucial for the growing repaired tetralogy of Fallot population at risk of major adverse clinical outcomes; however, current tools are hindered by lack of validation. This study aims to develop and validate a risk prediction model for death in the repaired tetralogy of Fallot population. Methods and Results Patients with repaired tetralogy of Fallot enrolled in the INDICATOR (International Multicenter Tetralogy of Fallot Registry) cohort with clinical, arrhythmia, cardiac magnetic resonance, and outcome data were included. Patients from London, Amsterdam, and Boston sites were placed in the development cohort; patients from the Toronto site were used for external validation. Multivariable Cox regression was used to evaluate factors associated with time from cardiac magnetic resonance until the primary outcome: all‐cause death. Of 1552 eligible patients (n=1221 in development, n=331 in validation; median age at cardiac magnetic resonance 23.4 [interquartile range, 15.6–35.6] years; median follow up 9.5 years), 102 (6.6%) experienced the primary outcome. The multivariable Cox model performed similarly during development (concordance index, 0.83 [95% CI, 0.78–0.88]) and external validation (concordance index, 0.80 [95% CI, 0.71–0.90]) and identified older age at cardiac magnetic resonance, obesity, type of tetralogy of Fallot repair, higher right ventricular end‐systolic volume index, and lower biventricular global function index as independent predictors of death. A risk‐scoring algorithm dividing patients into low‐risk (score ≤4) versus high‐risk (score >4) groups was validated to effectively discriminate risk of death (15‐year survival of 95% versus 74%, respectively; P

With over 9 million cows in the United States, Holstein is the dominant breed in the US dairy population; however, the US Jersey population is growing. The objective of this study was to determine the profitability of Holstein and Jersey cows managed similarly on the same farms. Holstein and Jersey economic performance was compared within 3 north central US dairies, each milking more than 500 cows. The herds' average distribution was 21% Jersey (27 ± 0.67 kg/d milk, 4.92% ± 0.24 fat, 3.72% ± 0.03 protein) and 79% Holstein (37 ± 1.98 kg/d milk, 3.85% ± 0.21 fat, 3.17% ± 0.17 protein). A comparative budget approach was used to assess economic factors that differed between the breeds on a per cow annual basis, based on the assumption that an existing farm would be constrained by stalls and parlor to an equal number of Jersey and Holstein cows. Data from 2020 were gathered from farm management software, on-farm evaluations, and producer interviews. Sensitivity analysis was performed to determine which conditions would lead to different conclusions. Factors considered in the analysis included milk and component production, milk bonuses, ration prices, and dry matter (DM) intake. In a 2021 price scenario, Holstein cows ranged from $345 to $601 more profitable than Jersey cows on a per cow annual basis. Although Jersey cows had an advantage in component concentration, Holstein cows produced 13 ± 4.7% more fat and 22 ± 6.6% more protein annually due to greater milk yield. This accounted for most of the profitability advantage for Holsteins; 78% of the revenue advantage for Holstein cows came from increased component production. Few health and reproductive differences were found. The sensitivity analysis revealed, if all other factors remained the same, Jersey profitability would equal that of Holstein if any of the following changes occurred (assuming no change in Holstein metrics): mean Jersey milk production increased to 31 kg/d; milk price adjustments decreased from −$0.008 to −$0.11 per kg fluid milk; lactating cow ration price increased from $0.27 per kg DM to $0.53 per kg DM; or Jersey DM intake decreased from 20 to 15 kg/d. The study did not consider crossbred profitability or new infrastructure investments. In conclusion, Holstein cows were more profitable than Jersey cows on these 3 north central US dairies.

Abstract Watershed nutrient management often focuses on actions that reduce the movement of nitrogen (N) and phosphorus (P) from agricultural lands into streams. One area of management focus is the buffer of land adjacent to streams. Wetlands and forests in this buffer can intercept and retain N and P from the landscape. In addition to directly intercepting agricultural nutrients, natural habitats in the buffer can alter stream geomorphology and influence the in‐stream processing and transformation of N and P to less labile and mobile forms. Here, we assess the influence of buffer land cover on in‐stream processing of N and P. We measured nutrient dynamics in the water column and sediments of agricultural streams in the Fox River and Duck Creek watersheds (WI, USA) during the growing season. In these streams, water column processing was low, possibly due to a lack of primary producers in the water column. Water column P processing was weakly associated with wetland land cover in the buffer, but buffer land cover had no clear effect on inorganic N processing. On the other hand, sediments were almost always a source of inorganic P and a sink for inorganic N. Sediment P release was higher in streams with more agricultural land cover in the buffer. Sediments in streams with agricultural land cover in the buffer also removed more nitrate, even after accounting for the greater availability of nitrate in those streams. The buffer land cover conditions we quantified occupy a very small portion of the overall watershed (100 m wide, for 1 km upstream of the study site) but nevertheless appear to influence in‐stream cycling of N and P. For P management, reducing agricultural land cover in buffers is already a priority due to the ability of wetlands and forests to intercept nutrients, but this study suggests there may be some additional benefit due to changes in in‐stream P processing.

Objective: To evaluate the ability of DynaMedex, an evidence-based drug and disease Point of Care Information (POCI) resource, in answering clinical queries using keyword searches. Methods: Real-world disease-related questions compiled from clinicians at an academic medical center, DynaMedex search query data, and medical board review resources were categorized into five clinical categories (complications & prognosis, diagnosis & clinical presentation, epidemiology, prevention & screening/monitoring, and treatment) and six specialties (cardiology, endocrinology, hematology-oncology, infectious disease, internal medicine, and neurology). A total of 265 disease-related questions were evaluated by pharmacist reviewers based on if an answer was found (yes, no), whether the answer was relevant (yes, no), difficulty in finding the answer (easy, not easy), cited best evidence available (yes, no), clinical practice guidelines included (yes, no), and level of detail provided (detailed, limited details). Results: An answer was found for 259/265 questions (98%). Both reviewers found an answer for 241 questions (91%), neither found the answer for 6 questions (2%), and only one reviewer found an answer for 18 questions (7%). Both reviewers found a relevant answer 97% of the time when an answer was found. Of all relevant answers found, 68% were easy to find, 97% cited best quality of evidence available, 72% included clinical guidelines, and 95% were detailed. Recommendations for areas of resource improvement were identified. Conclusions: The resource enabled reviewers to answer most questions easily with the best quality of evidence available, providing detailed answers and clinical guidelines, with a high level of replication of results across users.

Abstract The evolution of ice‐phase particles within precipitating clouds depends on the environmental properties of the cloud and on physical characteristics of the particles themselves, which can be modified by airflow over steep terrain. Through employing a unique Lagrangian particle‐based precipitation model, this study investigates the sensitivities in ice‐phase particle growth and transport due to variabilities in riming processes over an orographic barrier. This analysis is applied to two wintertime stratiform cyclones sampled by in situ aircraft over windward slopes during the Olympic Mountains Experiment. For both events, we simulate the ice‐phase particle evolution and trajectory within a two‐dimensional prescribed state representative of median observed cloud properties. Sensitivity simulations were constructed based on observed variabilities in supercooled liquid water (SLW) properties and its vertical extent above the melting level. Perturbations of SLW concentration equivalent to the 85th and 15th percentiles of observed values, which typically amounted to a change of less than 0.05 g m−3, resulted in respective increases or decreases in the ice‐phase contribution to surface precipitation mass by as much as 50% and horizontal particle trajectories differences exceeding 10 km. Similar sensitivities were found in response to varying the vertical extent of SLW above the melting level and to adjustments in mean SLW droplet size. The significant precipitation response to small variations in cloud properties principally arises from changing rates of rime mass accumulation and correspondingly, increases in particle fall speed. Considerations for the numerical representation of the riming process and its complex effects on precipitation are discussed.

ABSTRACT: Background: Identification of risk factors for biventricular (BiV) repair in children with hypoplastic left ventricles (HLV) has been challenging. We sought to identify preoperative cardiovascular magnetic resonance (CMR) predictors of outcome in patients with HLVs who underwent BiV repair, with a focus on the mitral valve (MV). Methods: Single-center retrospective analysis of preoperative CMRs on patients with HLV (≤50 mL/m2) and no endocardial fibroelastosis who underwent BiV repair from 2005–2022. CMR measurements included MV orifice area in diastole. The primary composite outcome included time to death, transplant, BiV takedown, heart failure admission, left atrial decompression, or unexpected reoperation; and the secondary outcome included more than or equal to moderate mitral stenosis and/or regurgitation. Results: Median follow-up was 0.7 (interquartile range 0.1, 2.2) years. Of 122 patients [59 atrioventricular canal (AVC) and 63 non-AVC] age 3 ± 2.8 years at the time of BiV repair, freedom from the primary outcome at 2 years was 53% for AVC and 69% for non-AVC (log rank p = 0.12), and freedom from the secondary outcome at 2 years was 49% for AVC and 79% for non-AVC (log rank p

Abstract Background Lymphatic complications are common in patients with Fontan circulation. Three-dimensional balanced steady-state free precession (3D bSSFP) angiography by cardiovascular magnetic resonance (CMR) is widely used for cardiovascular anatomical assessment. We sought to determine the frequency of thoracic duct (TD) visualization using 3D bSSFP images and assess whether TD characteristics are associated with clinical outcomes. Methods This was a retrospective, single-center study of patients with Fontan circulation who underwent CMR. Frequency matching of age at CMR was used to construct a comparison group of patients with repaired tetralogy of Fallot (rTOF). TD characteristics included maximum diameter and a qualitative assessment of tortuosity. Clinical outcomes included protein-losing enteropathy (PLE), plastic bronchitis, listing for heart transplantation, and death. A composite outcome was defined as presence of any of these events. Results The study included 189 Fontan patients (median age 16.1 years, IQR 11.0–23.2 years) and 36 rTOF patients (median age 15.7 years, IQR 11.1–23.7 years). The TD diameter was larger (median 2.50 vs. 1.95 mm, p = 0.002) and more often well visualized (65% vs. 22%, p

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.

Abstract Background To evaluate the relationship between measures of neuromuscular impairment and limb accelerations (LA) collected during sleep among individuals with chronic spinal cord injury (SCI) to provide evidence of construct and concurrent validity for LA as a clinically meaningful measure. Methods The strength (lower extremity motor score), sensation (summed lower limb light touch scores), and spasticity (categorized lower limb Modified Ashworth Scale) were measured from 40 adults with chronic (≥ 1 year) SCI. Demographics, pain, sleep quality, and other covariate or confounding factors were measured using self-report questionnaires. Each participant then wore ActiGraph GT9X Link accelerometers on their ankles and wrist continuously for 1–5 days to measure LA from movements during sleep. Regression models with built-in feature selection were used to determine the most relevant LA features and the association to each measure of impairment. Results LA features were related to measures of impairment with models explaining 69% and 73% of the variance (R²) in strength and sensation, respectively, and correctly classifying 81.6% (F1-score = 0.814) of the participants into spasticity categories. The most commonly selected LA features included measures of power and frequency (frequency domain), movement direction (correlation between axes), consistency between movements (relation to recent movements), and wavelet energy (signal characteristics). Rolling speed (change in angle of inclination) and movement smoothness (median crossings) were uniquely associated with strength. When LA features were included, an increase of 72% and 222% of the variance was explained for strength and sensation scores, respectively, and there was a 34% increase in spasticity classification accuracy compared to models containing only covariate features such as demographics, sleep quality, and pain. Conclusion LA features have shown evidence of having construct and concurrent validity, thus demonstrating that LA are a clinically-relevant measure related to lower limb strength, sensation, and spasticity after SCI. LA may be useful as a more detailed measure of impairment for applications such as clinical prediction models for ambulation.

Abstract Background Cross-sectional studies have reported that ventricular dilation and dysfunction are associated with adverse clinical outcome in Fontan patients; however, longitudinal changes and their relationship with outcome are not known. Methods This was a single-center retrospective analysis of Fontan patients with at least 2 cardiovascular magnetic resonance (CMR) scans without intervening interventions. Serial measures of end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), indexed mass (mass i ), mass-to-volume ratio, and end-systolic wall stress (ESWS) were used to estimate within-patient change over time. Changes were compared for those with and without a composite outcome (death, heart transplant, or transplant listing) as well as between patients with left (LV) and right ventricular (RV) dominance. Results Data from 156 patients were analyzed with a mean age at 1st CMR of 17.8 ± 9.6 years. 490 CMRs were included with median of 3 CMRs/patient (range 2–9). On regression analysis with mixed effects models, volumes and ESWS increased, while mass, mass-to-volume ratio, and EF decreased over time. With a median follow-up of 10.2 years, 14% met the composite outcome. Those with the composite outcome had a greater increase in EDVI compared to those without (4.7 vs. 0.8 ml/BSA1.3/year). Compared with LV dominance, RV dominance was associated with a greater increase in ESVI (1.4 vs. 0.5 ml/BSA1.3/year), a greater decrease in EF (− 0.61%/year vs. − 0.24%/year), and a higher rate of the composite outcome (21% vs. 8%). Conclusions Ventricles in the Fontan circulation exhibit a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and decrease in EF, mass index, and mass-to-volume ratio. Those with death or need for heart transplantation have a faster increase in EDVI. Patients with rapid increase in EDVI (> 5 ml/BSA1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. RV dominance is associated with worse clinical outcomes and remodeling compared to LV dominance.

Abstract Three‐dimensional (3D) charge‐written periodic peak and valley nanoarray surfaces are fabricated on a (112¯0) ZnO single crystal grown via chemical vapor transport. Because the grown ZnO crystals exhibit uniform n‐type conduction, 3D periodic nanoarray patterns are formed via oxygen annealing. These periodically decorated structures show that the peak arrays are conducting at the nanoampere level, whereas the valley arrays are less conductive. Energy dispersive spectroscopy indicates that the valley arrays are deficient in zinc by ≈4–6 at%, and that the peak arrays are deficient in oxygen, respectively. Kelvin probe force microscopy reveals the presence of periodic wiggles featuring variations of ≈70–140‐meV between the peak and valley arrays. A significant decrease in the Fermi level of the valley region is observed (≈190 meV), which corresponds to a high zinc vacancy doping density of 2 × 1018 cm−3. This result indicates the periodic generation of an extremely large electric field (≈11 000 V cm−1) in the vicinity of the peak–valley arrays. Computational analysis corroborates the experimentally observed generation of VZn and the preferential formation of surface protrusions on ZnO (112¯0) rather than on (0001), based on surface effects, along with the generation of peak and valley features.

The product formed by base-induced dimerisation of (2S,5S)-2-tert-butyl-5-methyl-1,3-dioxolan-4-one is shown by X-ray diffraction to be the title compound and not the isomeric fused-ring 1,3-dioxolane/1,3-dioxane-4-one structure proposed by previous researchers. The analogous compound derived from (2S,5S)-5-benzyl-2-tert-butyl-1,3-dioxolan-4-one has also been obtained and characterised.

Background: Over two-thirds of nursing home (NH) residents are eligible for palliative care (PC), yet few receive it, particularly outside of hospice. Little is known about the technical feasibility and acceptability of using telehealth for PC consultations in NHs. Objective: To determine the technical feasibility and acceptability of PC telehealth for NH residents seen by a PC team in the hospital in the previous 30 days. Design: Mixed methods study including data collection from field observations, focus groups about the telehealth experience with content analysis, and a web-based survey about technical feasibility and acceptability. Sample and Approach: Eighteen participants (six PC-eligible NH residents, one PC physician, five family members, six NH nurses) were recruited in 2016 to participate in one of six PC video visits followed by a video-based focus group and web-based survey. Results: All participants were comfortable with the PC video visit format, believed it could improve communication and care coordination, and reported they could see themselves using telehealth in the near future. For technical feasibility, audio quality was rated mostly good/very good (71%) and visual quality was rated fair (50%). Conclusions: PC video visits are technically feasible and acceptable to NH residents, families, and staff, representing an innovative and relatively low-cost opportunity to improve access to needed NH-based PC services. Assessing stakeholder perspectives on the use of this technology can help inform the selection of the proper telehealth platform to meet the clinical and infrastructure needs, as well as protocol modifications required before testing in a larger trial.

Defect-free surfaces with excess charge are typically described as a homogeneous 2D electron gas. Here, in contrast, the authors find that the KTaO3(001) surface hosts a charge density wave coexisting with a pattern of electron polarons, highly localized states of excess electrons bound to a lattice distortion.

BackgroundAccurate measurement of ventricular volumes is an important clinical imaging goal. Three-dimensional echocardiography (3DEcho) is used increasingly as it is more available and less costly than cardiac magnetic resonance (CMR). For the right ventricle (RV), the current practice is to acquire 3DEcho volumes from the apical view. However, in some patients the RV may be better seen from the subcostal view. Therefore, this study compared RV volume measurements from the apical vs. the subcostal view, using CMR as a reference standard.MethodsPatients

Abstract Background In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics. Methods Trophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC–MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student’s t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities. Results A total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways. Conclusions Overall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.

Rationale & Objective: We sought to elicit patient preferences regarding the use of plasma exchange in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and its tradeoffs of risk of kidney failure and risk of serious infection. Study Design: Patient survey. Setting & Participants: The online survey was circulated to adults with AAV via kidney and vasculitis networks in Canada, the United Kingdom, and the United States. Outcomes: Respondents reviewed the estimated 1-year risks of kidney failure and serious infection in AAV with and without plasma exchange across 5 serum creatinine categories (150, 250, 350, 450, and 600 μmol/L). For each scenario, participants indicated whether or not they would choose plasma exchange. Analytical Approach: Responses were assessed with multilevel multivariable logistic regression models to identify predictors of respondent choice regarding treatment with plasma exchange. Results: The 470 respondents from the 13 countries (United States 61.7%, United Kingdom 20.0%, Canada 13.8%, and other countries 4.5%) had a mean age of 58.6 (SD 14.3) years, 70.2% women. Respondents were more likely to choose plasma exchange in scenarios at high risk of kidney failure and serious infection (creatinine level of 350 or 450 μmol/L) compared with lower risk scenarios or the highest risk scenario. However, 145 (30.9%) chose plasma exchange across all scenarios, whereas 80 (17.0%) declined plasma exchange across all scenarios. Respondents from the United Kingdom (OR, 2.61; 95% CI, 1.09-6.22) who received previous dialysis (OR, 2.70; 95% CI, 1.12-6.52) or received previous plasma exchange (OR, 5.62; 95% CI, 2.72-11.61) were more likely to choose plasma exchange, whereas older respondents (OR, 0.98; 95% CI, 0.96-0.99 per 1 year increase) were less likely. Limitations: Unclear generalizability to non–English-speaking, older, and less health literate adults, possible responder bias, survivor bias, lack of individualized risk assessments for kidney failure, and serious infection. Conclusions: Patients with AAV do not express a consistent choice for plasma exchange, which highlights the need for shared decision making.

IntroductionNRAS mutations are common in melanoma and confer a worse prognosis. Although most patients with metastatic melanoma receive immune checkpoint inhibitors (ICIs), the impact of NRAS mutational status on their efficacy remains under debate.MethodsWe performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by NRAS mutational status in patients with melanoma treated with any line of ICI. At least two reviewers independently screened studies using Covidence software, extracted data, and assessed risk of bias. Standard meta-analysis was performed in R with sensitivity analysis and tests for bias.ResultsData on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare NRAS-mutant and NRAS-wildtype melanoma. The objective response rate was 1.28 (95% confidence interval: 1.01–1.64). Sensitivity analysis identified the study by Dupuis et al. with influential impact on the pooled effect size and heterogeneity, favoring NRAS-mutant melanoma.DiscussionIn this meta-analysis evaluating the impact of NRAS mutational status on objective response to ICIs in metastatic melanoma, NRAS-mutant cutaneous melanoma demonstrated an increased likelihood of partial or complete tumor response, relative to NRAS-wildtype cutaneous melanoma. Genomic screening for NRAS mutations in patients with metastatic melanoma may improve predictive ability when initiating ICIs.

A morphological and molecular analysis of Gryon Haliday (Platygastroidea, Scelionidae) was conducted to provide a taxonomic and phylogenetic context for a species under evaluation as a biological control agent of Bagrada hilaris (Burmeister) (Hemiptera, Pentatomidae). Our analysis revealed that Gryon is polyphyletic and that the biological control agent is not G. gonikopalense, a name that was tentatively applied to this species in 2019. We here describe this species as new, Gryon aetherium Talamas sp. nov., and resurrect the generic name Hadronotus Förster. Morphological characters that delimit our concepts of Gryon and Hadronotus are presented. Based on morphological characters and multilocus phylogenies, we determined that five presently valid scelionid genera belong within Gryon. In total, 15 species are transferred into Gryon from these genera, 215 species are transferred from Gryon to Hadronotus, and 6 species are transferred from Gryon to Dyscritobaeus Perkins. Specimens collected during field studies in California and reevaluation of specimens determined as G. myrmecophilum in Mexico reveal that G. aetherium is adventive in North America.

Abstract Background A synthesis of real-world discontinuation and switching patterns among triptan users and rates of acute medication use among patients with medication overuse headache (MOH) is needed to better understand the burden among patients with migraine. The study objectives were to: (1) synthesize rates of switching and discontinuation from triptans; (2) characterize acute medication use among patients with MOH; and (3) describe the associated burden. Methods A systematic literature review was conducted, under the Preferred Reporting Items for Systematic Review guidelines, using MEDLINE/EMBASE from database inception to July 2019. The search strategy targeted studies of adults with migraine, and included terms related to migraine and its treatment. Continuous variables were summarized using means, standard deviations, and ranges. Dichotomous and categorical variables were summarized using the number and proportion of individuals. Results Twenty studies were included; seven describing patterns of switching and discontinuation among triptan users, and 13 characterizing triptan overuse among patients with MOH. High rates of switching to non-specific acute medications and low two-year retention rates were reported; among US samples switching to opioids at the first refill (18.2%) or after 1-year (15.5%) was frequent. Compared to persistent use of triptans, switchers experienced greater headache related impact and either no improvement or increased headache-related disability. Rates of medication overuse by agent among patients with MOH varied greatly across the included studies, and only one study described factors associated with the risk of MOH (e.g. duration of medication overuse). Medication agent, increased headache frequency (p = .008), and increased disability (p = .045) were associated with unsuccessful withdrawal; patients overusing triptans were more successful at withdrawal than those overusing opioids or combination analgesics (P