Spinal Muscular Atrophy Update in Best Practices: Recommendations for Treatment Considerations.

Background and Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by biallelic variants of the Survival Motor Neuron 1 gene (SMN1) that affects approximately 1 in 15,000 live births. Availability of 3 SMN-enhancing treatments for SMA has led to urgency to review how clinicians and patients use these treatments for SMA, while additional research and real-world data and experience are being collected. This work describes important factors to assist with decision-making for SMN-enhancing treatments. Methods: A systematic literature review was conducted on SMN-enhancing treatments for SMA and related studies. A working group of American and European health care providers with expertise in SMA care identified barriers and developed recommendations through a modified Delphi technique with serial surveys and feedback through virtual meetings to fill gaps for information where evidence is limited. A community working group of an individual living with SMA and caregivers provided insight and perspective on SMA treatments and support through a virtual meeting to guide recommendations. Results: The health care provider working group and the community working group agreed that when determining whether to start, change, add, or discontinue a treatment, essential considerations include patient and family/caregiver perspective, and treatment safety and side effects. When initiating treatment for patients newly diagnosed with SMA, important patient characteristics are age and Survival Motor Neuron 2 gene (SMN2) copy number. Furthermore, when initiating, changing, or adding treatment, current clinical status and comorbidities drive decision-making. When considering a medication or treatment plan change, unless there is an urgent indication, a treatment and associated patient outcomes should be monitored for a minimum of 6-12 months. When determining a treatment plan with an adolescent or adult with SMA, consider factors such as quality of life, burden vs benefit of treatment, and reproductive issues. Access to care coordination and interdisciplinary/multidisciplinary care are essential to treatment success. Discussion: Sharing information about current knowledge of treatments and shared decision-making between health care providers and patients living with SMA and caregivers are essential to overcoming barriers to providing SMN-enhancing treatments.

Mortality associated with clozapine: what is the evidence?

While clozapine has risks, relative risk of fatality is overestimated. The UK pharmacovigilance programme is efficient, but comparisons with other drugs can mislead because of reporting variations. Clozapine actually lowers mortality, partly by reducing schizophrenia-related suicides, but preventable deaths still occur. Clozapine should be used earlier and more widely, but there should be better monitoring and better management of toxicity.

Real-world Decision-making Process for Stereotactic Body Radiotherapy Versus Minimally Invasive Surgery in Early-stage Lung Cancer Patients.

OBJECTIVE: To generate a prediction model for selection of treatment modality for early-stage non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Stereotactic body radiotherapy (SBRT) and minimally invasive surgery (MIS) are used in the local treatment of early-stage NSCLC. However, selection of patients for either SBRT or MIS remains challenging, due to the multitude of factors influencing the decision-making process. METHODS: We analyzed 1291 patients with clinical stage I NSCLC treated with intended MIS or SBRT from January 2020 to July 2023. A prediction model for selection for SBRT was created based on multivariable logistic regression analysis. The receiver operating characteristic curve analysis stratified the cohort into 3 treatment-related risk categories. Post-procedural outcomes, recurrence and overall survival (OS) were investigated to assess the performance of the model. RESULTS: In total, 1116 patients underwent MIS and 175 SBRT. The prediction model included age, performance status, previous pulmonary resection, MSK-Frailty score, FEV1 and DLCO, and demonstrated an area-under-the-curve of 0.908 (95%CI, 0.876-0.938). Based on the probability scores (n=1197), patients were stratified into a low-risk (MIS, n=970 and SBRT, n=28), intermediate-risk (MIS, n=96 and SBRT, n=53) and high-risk category (MIS, n=10 and SBRT, n=40). Treatment modality was not associated with OS (HR of SBRT, 1.67 [95%CI: 0.80-3.48]; P=0.20). CONCLUSION: Clinical expertise can be translated into a robust predictive model, guiding the selection of stage I NSCLC patients for MIS versus SBRT and effectively categorizing them into three distinct risk groups. Patients in the intermediate category could benefit most from multidisciplinary evaluation.

Impact of a Design Thinking Educational Activity on Graduate Students' Knowledge, Confidence, and Perceived Benefits.

BACKGROUND: Design Thinking is gaining recognition as an innovative and creative approach to problem solving. Though nurse leaders need problem solving tools to address health care challenges, Design Thinking concepts are not commonly taught in nursing education. To introduce graduate level nursing students to Design Thinking, we held an educational activity focused on this content as part of required coursework. PURPOSE: The purpose was to describe and compare outcomes of a Design Thinking educational activity on students' perceived knowledge, confidence, and benefits to nursing practice. METHODS: Graduate level nursing students participated in a 3-hour educational activity. After the session, students completed an anonymous 10-item survey of their perceptions of the educational activity. RESULTS: Students reported increased knowledge and confidence of communication strategies and Design Thinking concepts that would benefit their practice. CONCLUSION: Nurse educators should include Design Thinking teaching and learning strategies in their programs.

"Will ICER's 'shared savings' approach decrease value-based prices most for the most severe diseases?"

OBJECTIVES: To identify the types of disease most likely to be impacted by the Institute for Clinical and Economic Review's (ICER) shared savings assumptions. METHODS: For diseases with treatments that were FDA-approved between 2019 and 2023, annual direct and indirect economic burden and characteristics of each disease were extracted from peer-reviewed literature. ICER's shared savings methodology was applied two ways: 50/50 shared savings and $150,000 cost-offset cap. The primary outcome was the difference in eligible cost savings provided by a hypothetical disease cure under ICER's 2 shared savings methods. Characteristics of diseases most impacted by these 2 methods were evaluated descriptively. RESULTS: FDA approved 260 therapies for 89 unique diseases between 2019 and 2023. Shared savings reduced value of a hypothetical cure for hemophilia A most (50/50 method: -$367,670 per year; cap method: -$585,340 per year), followed by acute hepatic porphyria (50/50 method: -$333,948; cap method: -$517,896) and paroxysmal nocturnal hemoglobinuria (50/50 method: -$291,997; cap method: -$433,993). Compared to diseases with annual burdens <$150,000, those ≥$150,000 had earlier disease onset by 22.0 years (age 12.3 vs. 34.3), lower life expectancy by 10.6 years (55.8 vs. 66.4 years), and lower disease prevalence (4.7 vs. 1981.5 per 100,000). Shared savings' impact on health benefit price benchmarks was projected to be larger for diseases with shorter life expectancy (ρ=-0.319; p=0.005), worse quality-of-life (ρ=-0.263; p=0.020), and lower prevalence (ρ=-0.418; p<0.001). CONCLUSIONS: ICER's shared savings assumptions would most likely have the largest negative impact on health benefit price benchmarks for rare, severe, and pediatric diseases.

Efficacy and safety of covered self-expandable metal stent for malignant hilar biliary obstruction: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Covered self-expanding metal stents (C-SEMS) are used for malignant hilar biliary obstruction (MHBO) management. Despite increasing evidence, comprehensive evaluation of the efficacy and safety of C-SEMS in MHBO management is lacking. METHODS: PubMed, EMBASE, and the Cochrane Library were screened up to March 31, 2024 for studies including MHBO treated by a C-SEMS. Studies meeting predefined inclusion criteria, including adult MHBO patients treated with C-SEMS placement, reporting technical success, clinical success, and adverse event rates, were selected. Data synthesis and statistical analysis were performed using the random effects model, with heterogeneity and publication bias assessment. RESULTS: From 401 articles, seven studies were included. Pooled technical and clinical success rate of C-SEMS was 96.7% (95% CI 92.6-98.6%, I2=0%) and 91.6% (95% CI 86.1-95.0%, I2=0%). Overall adverse events were reported in 16.6% (95% CI 11.2-23.9%, I2=24%) of cases which included cholangitis (7.4%), pancreatitis (5.9%), liver abscess (5.9%), and cholecystitis (2.8%). Stent migration and recurrent biliary obstruction were observed in 8.9% and 49.6% of cases, respectively, with a median time to recurrent biliary obstruction of 142 days. Reintervention was successful in 92.5% of cases (95% CI 83.1-96.9%, I2=0%) CONCLUSION: Our meta-analysis revealed high technical and clinical success rates of C-SEMS in MHBO. Adverse events, notably cholangitis, cholecystitis, and pancreatitis were <10%. RBO and stent migration was mitigated by C-SEMS removal and successful reintervention. Our findings highlight the efficacy and safety of C-SEMS in managing MHBO, warranting further research to optimize treatment strategies.

Single­Dose Pharmacokinetics and Safety of the Oral Galectin­3 Inhibitor, Selvigaltin (GB1211), in Participants with Hepatic Impairment.

BACKGROUND AND OBJECTIVES: Selvigaltin (GB1211), an orally available small molecule galectin-3 inhibitor developed as a treatment for liver fibrosis and cirrhosis, was evaluated to assess the effect of hepatic impairment on its pharmacokinetics and safety to address regulatory requirements. METHODS: GULLIVER-2 was a Phase Ib/IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing pharmacokinetics (plasma [total and unbound] and urine), safety, and tolerability of 100 mg oral selvigaltin in participants with moderate (Child-Pugh B, Part 1) or severe (Child-Pugh C, Part 3) hepatic impairment, compared with healthy-matched participants (n = 6 each). RESULTS: All participants received selvigaltin and completed the study. No adverse events were reported. The median time to reach maximum total plasma concentration following drug administration was of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma exposure was higher for participants with hepatic impairment compared with controls. Whilst maximum plasma concentration (Cmax) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUC∞) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs 16.38 h). In Child-Pugh C participants, Cmax increased by ~ 1.3-fold, AUC∞ increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs 16.14 h). No trend was observed in plasma unbound fractions or urinary excretion of unchanged selvigaltin in either group. CONCLUSION: Hepatic impairment increased selvigaltin exposure without safety concerns. These data can inform dose recommendations for future clinical programmes. TRIAL REGISTRATION: Clinicaltrials.gov NCT05009680.

Interfacial Stress Transfer and Fracture in van der Waals Heterostructures.

Artificially stacking 2D materials (2DMs) into vdW heterostructures creates materials with properties not present in nature that offer great potential for various applications such as flexible electronics. Properties of such stacked structures are controlled largely by the interfacial interactions and the structural integrity of the 2DMs. In spite of their crucial roles, interfacial stress transfer and the failure mechanisms of the vdW heterostructures, particularly during deformation, have not been well addressed so far. In this work, the interfacial stress transfer and failure mechanisms of a MoS2/graphene vdW heterostructure are studied, through the strain distributions both laterally in individual 2DMs and vertically across different 2DMs revealed in-situ. The fracture of the MoS2 and the associated states of stress and strain are monitored experimentally. This enables various interfacial properties, such as the interfacial shear strength and interfacial fracture energy, to be estimated. Based only on the measured strength and interfacial properties of a single vdW heterostructure, a failure criterion is proposed to predict the failure mechanisms of similar vdW heterostructures with any lateral dimensions. This work provides an insight to the deformation micromechanics of vdW heterostructures that are of great value for their miniaturization and applications, especially in flexible electronics.

Central tendency and serial dependence in vestibular path integration.

Path integration, the process of updating one's position using successive self-motion signals, has previously been studied using visual distance reproduction tasks in which optic flow patterns provide information about traveled distance. These studies have reported that reproduced distances show two types of systematic biases: central tendency and serial dependence. In the present study, we investigated whether these biases are also present in vestibular path integration. Participants were seated on a linear motion platform and performed a distance reproduction task in total darkness. The platform first passively moved the participant a pre-defined stimulus distance which they then actively reproduced by steering the platform back the same distance. Stimulus distances were sampled from short- and long-distance probability distributions and presented in either a randomized order or in separate blocks to study the effect of presentation context. Similar to the effects observed in visual path integration, we found that reproduced distances showed an overall positive central tendency effect as well as a positive, attractive serial dependence effect. Furthermore, reproduction behavior was affected by presentation context. These results were mostly consistent with predictions of a Bayesian Kalman-filter model, originally proposed for visual path integration.

A chiral hydrogen atom abstraction catalyst for the enantioselective epimerization of meso-diols.

Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes meso-diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol. This results in an enantioselective epimerization process, forming the chiral diastereomer with high enantiomeric excess. Cyclic and acyclic 1,2-diols are compatible, as are acyclic 1,3-diols. Additionally, we demonstrate the viability of combining our approach with carbon-carbon bond formation in Giese addition. Given the increasing number of synthetic methods involving hydrogen atom transfer steps, we anticipate that this work will have a broad impact in the field of enantioselective radical chemistry.

Density Spectral Array EEG for Sleep Staging in Pediatric Patients.

PURPOSE: Sleep is an essential physiologic process, which is frequently disrupted in children with illness and/or injury. Accurate identification and quantification of sleep may provide insights to improve long-term clinical outcomes. Traditionally, however, the identification of sleep stages has relied on the resource-intensive and time-consuming gold standard polysomnogram. We sought to use limited EEG data, converted into density spectrum array EEG, to accurately identify sleep stages in a clinical pediatric population. METHODS: We reviewed 87 clinically indicated pediatric polysomnographic studies with concurrent full montage EEG, between March 2017 and June 2020, of which 11 had normal polysomnogram and EEG interpretations. We then converted the EEG data of those normal studies into density spectral array EEG trends and had five blinded raters classify sleep stage (wakefulness, nonrapid eye movement [NREM] 1, NREM 2, NREM 3, and rapid eye movement) in 5-minute epochs. We compared the classified sleep stages from density spectral array EEG to the gold standard polysomnogram. RESULTS: Inter-rater reliability was highest (κ = 0.745, P < 0.0001) when classifying state into wakefulness, NREM sleep, and rapid eye movement sleep. Agreement between group classification and polysomnogram was highest (κ = 0.873, [0.819, 0.926], P < 0.0001) when state was classified into wakefulness and sleep and was lowest (κ = 0.674 [0.645, 0.703], P < 0.0001) when classified into wakefulness, NREM 1, NREM 2, NREM 3, and rapid eye movement. The most common error that raters made was overscoring of NREM 1. CONCLUSIONS: Density spectral array EEG can be used to identify sleep stages in clinical pediatric patients without relying on traditional polysomnography.

Global Progression Rates of Precursor Lesions for Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Whether gastric cancer (GC) precursor lesions progress to invasive cancer at similar rates globally remains unknown. We conducted a systematic review and meta-analysis to determine the progression of precursor lesions to GC in countries with low versus medium/high incidence. METHODS: We searched relevant databases for studies reporting the progression of endoscopically confirmed precursor lesions to GC. Studies were stratified by low (<6 per 100,000) or medium/high (≥6 per 100,000) GC incidence countries. Random-effects models were used to estimate the progression rates of atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia to GC per 1,000 person-years. RESULTS: Among the 5,829 studies identified, 44 met our inclusion criteria. The global pooled estimates of the progression rate per 1,000 person-years were 2.09 (95% CI 1.46-2.99), 2.89 (2.03-4.11) and 10.09 (5.23-19.49) for AG, IM, and dysplasia respectively. The estimated progression rates per 1,000 person-years for low versus medium/high GC incidence countries, respectively, were 0.97 (0.86-1.10) vs. 2.47 (1.70-2.99) for AG (p<0.01); 2.37 (1.43-3.92) vs. 3.47 (2.13-5.65) for IM (p=0.29); and 5.51 (2.92-10.39) vs. 14.80 (5.87-37.28) for dysplasia (p=0.08). There were no differences for progression of AG between groups when high quality studies were compared. CONCLUSION: Similar progression rates of IM and dysplasia were observed among low and medium/high GC incidence countries. This suggests that the potential benefits of surveillance for these lesions in low-risk regions may be comparable to those of population-wide interventions in high-risk regions. Further prospective studies are needed to confirm these findings and inform global screening and surveillance guidelines.

A scalable approach to assess the safety of recently marketed systemic treatments for atopic dermatitis in clinical practice.

Targeted systemic immune-modulating drugs (IMDs) to treat atopic dermatitis (AD) were highly efficacious in randomized trials. Trials with limited number of subjects leave questions about their safety. We describe a data and analytics structure for the production of timely, high-quality evidence on the comparative safety of recently approved IMDs in patients with AD in clinical practice. We established a series of sequential propensity score (PS)-balanced cohorts that grow in size with each annual data refresh. Nine health outcomes of interest plus conjunctivitis as a positive tracer outcome were identified. The initial treatment comparison was dupilumab, an interleukin-4/13 inhibitor, or tralokinumab, an interleukin-13 inhibitor, versus abrocitinib/upadacitinib, both JAK inhibitors. The first analysis cycle (December 2021-February 2023) compared 269 patients initiating JAK inhibitors and 2,650 initiating IL-4/IL-13 inhibitors. Patient characteristics were well balanced after PS-matching. Outpatient infections within 180 days occurred in 18% of JAK-1 inhibitor initiators versus 12% of dupilumab/ tralokinumab initiators (RR=1.50; 0.96 to 2.33) whereas acne risks were 7% vs. 3%, respectively (RR=2.29, 0.96 to 5.46). This sequential monitoring system will produce essential knowledge on the safety of IMDs to treat AD based on its growing study size of patients observed in clinical practice.

Epidemiology of Alcohol-Associated Liver Disease Including Increasing Burden in Young Adults and Females Especially Since Covid-19 Pandemic.

Alcohol-associated liver disease (ALD) was already on the rise globally when the advent of coronavirus disease 2019 further accelerated this trend. ALD has emerged as the leading cause for liver transplantation in the United States. The pandemic has not only intensified the prevalence of ALD but has also highlighted significant disparities in its impact, particularly, among young adults and women. This review aims to dissect the complex landscape of ALD, focusing on gender, race, and emerging risk factors in the context of the current global health crisis.

The Updated Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT 2.0).

The Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT) has been expanded to include more patients and CT attenuation correction imaging. We present the design and initial results from the updated registry. Methods: The updated REFINE SPECT is a multicenter, international registry with clinical data and image files. SPECT images were processed by quantitative software and CT images by deep learning software detecting coronary artery calcium (CAC). Patients were followed for major adverse cardiovascular events (MACEs) (death, myocardial infarction, unstable angina, late revascularization). Results: The registry included scans from 45,252 patients from 13 centers (55.9% male, 64.7 ± 11.8 y). Correlating invasive coronary angiography was available for 3,786 (8.4%) patients. CT attenuation correction imaging was available for 13,405 patients. MACEs occurred in 6,514 (14.4%) patients during a median follow-up of 3.6 y (interquartile range, 2.5-4.8 y). Patients with a stress total perfusion deficit of 5% to less than 10% (unadjusted hazard ratio [HR], 2.42; 95% CI, 2.23-2.62) and a stress total perfusion deficit of at least 10% (unadjusted HR, 3.85; 95% CI, 3.56-4.16) were more likely to experience MACEs. Patients with a deep learning CAC score of 101-400 (unadjusted HR, 3.09; 95% CI, 2.57-3.72) and a CAC of more than 400 (unadjusted HR, 5.17; 95% CI, 4.41-6.05) were at increased risk of MACEs. Conclusion: The REFINE SPECT registry contains a comprehensive set of imaging and clinical variables. It will aid in understanding the value of SPECT myocardial perfusion imaging, leverage hybrid imaging, and facilitate validation of new artificial intelligence tools for improving prediction of adverse outcomes incorporating multimodality imaging.

Diuretic dosing and outcomes with torsemide and furosemide following hospitalization for heart failure: The TRANSFORM-HF trial.

AIMS: The TRANSFORM-HF trial found no difference in clinical outcomes between torsemide versus furosemide after hospitalization for heart failure. This analysis aimed to assess the impact of diuretic dosing on the primary and secondary clinical outcomes. METHODS AND RESULTS: This post-hoc analysis of TRANSFORM-HF categorized patients into three groups by discharge diuretic dose: (1) ≤40 mg, (2) >40-80 mg, and (3) >80 mg of furosemide equivalents. The associations between discharge dose and 12-month clinical events, and change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), were assessed. Overall, 2379 patients were included, aged 65 years (interquartile range 56-75), 883 (37.1%) women, and 812 (34.2%) Black. Furosemide had adjusted hazard ratios (aHR) for all-cause mortality of 1.21 (95% confidence interval [CI] 0.91-1.59) for discharge dose group 2 and 1.40 (95% CI 1.04-1.88) for group 3, compared with group 1. For torsemide, aHRs were 1.74 (95% CI 1.32-2.30) for group 2 and 1.58 (95% CI 1.14-2.19) for group 3. No evidence of heterogeneity for the association between increased mortality and higher dose was found by loop diuretic type (pinteraction = 0.17). Higher doses of furosemide and torsemide were associated with increased risk of all-cause hospitalization and the composite of all-cause mortality and hospitalization, without evidence of heterogeneity by loop diuretic type (pinteraction > 0.2). Changes in KCCQ-CSS from baseline at 12 months was similar across dose groups for both drugs. CONCLUSION: Following hospitalization for heart failure, higher loop diuretic dosing was independently associated with worse clinical and patient-reported outcomes. The correlation between higher loop diuretic dose and outcomes was consistent, regardless of loop diuretic used.

Objective measurement of cough in pulmonary fibrosis: a cohort study - ImpaCT.

Using both objective cough monitoring and patient-reported outcomes measures, this study describes the burden of cough for patients with non-IPF pulmonary fibrosis https://bit.ly/3wFm0th.