Novel Textbook Outcomes following emergency laparotomy: Delphi exercise.

BACKGROUND: Textbook outcomes are composite outcome measures that reflect the ideal overall experience for patients. There are many of these in the elective surgery literature but no textbook outcomes have been proposed for patients following emergency laparotomy. The aim was to achieve international consensus amongst experts and patients for the best Textbook Outcomes for non-trauma and trauma emergency laparotomy. METHODS: A modified Delphi exercise was undertaken with three planned rounds to achieve consensus regarding the best Textbook Outcomes based on the category, number and importance (Likert scale of 1-5) of individual outcome measures. There were separate questions for non-trauma and trauma. A patient engagement exercise was undertaken after round 2 to inform the final round. RESULTS: A total of 337 participants from 53 countries participated in all three rounds of the exercise. The final Textbook Outcomes were divided into 'early' and 'longer-term'. For non-trauma patients the proposed early Textbook Outcome was 'Discharged from hospital without serious postoperative complications (Clavien-Dindo ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation or death). For trauma patients it was 'Discharged from hospital without unexpected transfusion after haemostasis, and no serious postoperative complications (adapted Clavien-Dindo for trauma ≥ grade III; including intra-abdominal sepsis, organ failure, unplanned re-operation on or death)'. The longer-term Textbook Outcome for both non-trauma and trauma was 'Achieved the early Textbook Outcome, and restoration of baseline quality of life at 1 year'. CONCLUSION: Early and longer-term Textbook Outcomes have been agreed by an international consensus of experts for non-trauma and trauma emergency laparotomy. These now require clinical validation with patient data.

Practice recommendations regarding parental presence in NICUs during pandemics caused by respiratory pathogens like COVID-19.

Aim: To co-create parental presence practice recommendations across Canadian NICUs during pandemics caused by respiratory pathogens such as COVID-19. Methods: Recommendations were developed through evidence, context, Delphi and Values and Preferences methods. For Delphi 1 and 2, participants rated 50 items and 20 items respectively on a scale from 1 (very low importance) to 5 (very high). To determine consensus, evidence and context of benefits and harms were presented and discussed within the Values and Preference framework for the top-ranked items. An agreement of 80% or more was deemed consensus. Results: After two Delphi rounds (n = 59 participants), 13 recommendations with the highest rated importance were identified. Consensus recommendations included 6 strong recommendations (parents as essential caregivers, providing skin-to-skin contact, direct or mothers' own expressed milk feeding, attending medical rounds, mental health and psychosocial services access, and inclusion of parent partners in pandemic response planning) and 7 conditional recommendations (providing hands-on care tasks, providing touch, two parents present at the same time, food and drink access, use of communication devices, and in-person access to medical rounds and mental health and psychosocial services). Conclusion: These recommendations can guide institutions in developing strategies for parental presence during pandemics caused by respiratory pathogens like COVID-19.

Type I Hsp40s/DnaJs aggregates exhibit features reminiscent of amyloidogenic structures.

A rise in temperature triggers a structural change in the human Type I 40 kDa heat shock protein (Hsp40/DnaJ), known as DNAJA1. This change leads to a less compact structure, characterized by an increased presence of solvent-exposed hydrophobic patches and ß-sheet-rich regions. This transformation is validated by circular dichroism, thioflavin T binding, and Bis-ANS assays. The formation of this ß-sheet-rich conformation, which is amplified in the absence of zinc, leads to protein aggregation. This aggregation is induced not only by high temperatures but also by low ionic strength and high protein concentration. The aggregated conformation exhibits characteristics of an amyloidogenic structure, including a distinctive X-ray diffraction pattern, seeding competence (which stimulates the formation of amyloid-like aggregates), cytotoxicity, resistance to SDS, and fibril formation. Interestingly, the yeast Type I Ydj1 also tends to adopt a similar ß-sheet-rich structure under comparable conditions, whereas Type II Hsp40s, whether human or from yeast, do not. Moreover, Ydj1 aggregates were found to be cytotoxic. Studies using DNAJA1- and Ydj1-deleted mutants suggest that the zinc-finger region plays a crucial role in amyloid formation. Our discovery of amyloid aggregation in a C-terminal deletion mutant of DNAJA1, which resembles a spliced homolog expressed in the testis, implies that Type I Hsp40 co-chaperones may generate amyloidogenic species in vivo.

Leveraging the outcome of a frontal bone tumor facial reconstruction case by a multimodal approach.

The importance of multimodality in the diagnosis and treatment of medical conditions cannot be overemphasized. Herewith a case of facial malignancy encompassing all stages of management and requiring multimodal approaches for diagnosis, oncological treatment, anatomical reconstruction, and ultimately aesthetics and "identity" is presented.

Unconventional acoustic wave propagation transitions induced by resonant scatterers in the high-density limit.

Experiments on ultrasound propagation through a gel doped with resonant encapsulated microbubbles provided evidence for a discontinuous transition between wave propagation regimes at a critical excitation frequency. Such behavior is unlike that observed for soft materials doped with non-resonant air or through liquid foams, and disagrees with a simple mixture model for the effective sound speed. Here, we study the discontinuous transition by measuring the transition as a function of encapsulated microbubble volume fraction. The results show the transition always occurs in the strong-scattering limit (l/λ < 1, l and λ are the mean free path and wavelength, respectively), that at the critical frequency the effective phase velocity changes discontinuously to a constant value with increasing microbubble volume fraction, and the measured critical frequency shows a power law dependence on microbubble volume fraction. The results cannot be explained by multiple scattering theory, viscous effects, mode decoupling, or a critical density of states. It is hypothesized the transition depends upon the microbubble on-resonance effective properties, and we discuss the results within the context of percolation theory. The results shed light on the discontinuous transition's physics, and suggest soft materials can be engineered in this manner to achieve a broad range of physical properties with potential application in ultrasonic actuators and switches.

Alternative Models of Nurse Staffing May Be Dangerous in High-Stakes Hospital Care.

BACKGROUND: Hospitals are resurrecting the outdated "team nursing" model of staffing that substitutes lower-wage staff for registered nurses (RNs). OBJECTIVES: To evaluate whether reducing the proportion of RNs to total nursing staff in hospitals is in the best interest of patients, hospitals, and payers. RESEARCH DESIGN: Cross-sectional, retrospective. SUBJECTS: In all, 6,559,704 Medicare patients in 2676 general acute-care US hospitals in 2019. MEASURES: Patient outcomes: in-hospital and 30-day mortality, 30-day readmission, length of stay, and patient satisfaction. Avoidable Medicare costs associated with readmissions and cost savings to hospitals associated with shorter stays are projected. RESULTS: A 10 percentage-point reduction in RNs was associated with 7% higher odds of in-hospital death, 1% higher odds of readmission, 2% increase in expected days, and lower patient satisfaction. We estimate a 10 percentage-point reduction in RNs would result in 10,947 avoidable deaths annually and 5207 avoidable readmissions, which translates into roughly $68.5 million in additional Medicare costs. Hospitals would forgo nearly $3 billion in cost savings annually because of patients requiring longer stays. CONCLUSIONS: Reducing the proportion of RNs in hospitals, even when total nursing personnel hours are kept the same, is likely to result in significant avoidable patient deaths, readmissions, longer lengths of stay, and decreased patient satisfaction, in addition to excess Medicare costs and forgone cost savings to hospitals. Estimates represent only a 10 percentage-point dilution in skill mix; however, the team nursing model includes much larger reductions of 40-50 percentage-points-the human and economic consequences of which could be substantial.

New Method to Probe the Surface Properties of Polymer Thin Films by Two-Dimensional (2D) Inverse Gas Chromatography (iGC).

Polymer-based functional surface coatings are extensively used in advanced technologies, including optics, energy, and environmental applications. Surface thermodynamic properties profoundly impact the molecular interactions that control interfacial behaviors, such as adhesion and wettability, which in turn dictate coating processes and performance. Conventionally, contact angle measurements are used to assess the surface energy of polymer films and coatings, where the wettability of a surface is assessed using probe fluids (liquid drops). However, contact angle measurement oftentimes can be nontrivial due to the roughness or chemical heterogeneity of the solid surface, as well as the potential for the liquid drop to swell or even dissolve the material being measured. Alternatively, inverse gas chromatography (iGC) is a versatile technique to measure surface thermodynamics and Lewis acid-base properties while also providing environmental control such as temperature and humidity. Despite these benefits, the application of iGC has been limited to powders or fibers, while the direct measurement of supported thin films or coatings is still a nascent area of research. This creates a challenge when using iGC as a comprehensive platform for measuring the physicochemical properties of solid surfaces. Here, we demonstrate how to effectively use iGC to characterize the surface energy of supported polymer thin films by using a two-dimensional (2D) film holder and modifying operational controls, such as the concentration range of the injected gas probe molecules. This enables the precise control of surface coverage required for analyzing samples having minimal surface area, such as thin films. Poly(methyl methacrylate) (PMMA) was employed as a benchmark to determine suitable iGC parameters and to validate our approach on polymer thin films. The seminal work presented here expands the capability of state-of-the-art iGC to embrace supported thin films (2D iGC) that could either be smooth or display texture/roughness (patterned films) as well as coatings with heterogeneous chemical/structural composition.

Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study.

PURPOSE: The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported. METHODS: Patients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m2 intravenous infusion on day 1) in 21-day cycles. Primary end point was overall survival (OS). Key secondary end points were investigator-assessed progression-free survival (PFS), objective response rate, patient-reported symptom assessment, and safety. RESULTS: In the intention-to-treat population (SG, n = 299; docetaxel, n = 304), 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary end point was not met. There was a numerical OS improvement for SG versus docetaxel (median, 11.1 v 9.8 months; hazard ratio [HR], 0.84 [95% CI, 0.68 to 1.04]; one-sided P = .0534), consistent across squamous and nonsquamous histologies. Median PFS was 4.1 versus 3.9 months (HR, 0.92 [95% CI, 0.77 to 1.11]). An OS benefit was observed for SG (n = 192) versus docetaxel (n = 191) in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen (3.5-month median OS increase; HR, 0.75 [95% CI, 0.58 to 0.97]); this was consistent across histologies. Among patients receiving SG and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs), respectively; 1.4% and 1.0%, respectively, had TRAEs leading to death. CONCLUSION: Although statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.

A systematic review of whether Health Impact Assessment frameworks support best practice principles.

OBJECTIVES: Health Impact Assessment (HIA) is an evidence-based approach to assess the likely public health impacts of a policy or plan in any sector. Several HIA frameworks are available to guide practitioners doing a HIA. This systematic review sought to determine whether these support practitioners to meet best practice principles defined by the International Association for Impact Assessment. STUDY DESIGN: This was a systematic review. METHODS: Three complementary search strategies were used to identify frameworks in June 2022. We used three databases to find completed HIAs published in the last five years and hand-searched their reference lists for frameworks. We also searched 23 HIA repositories using Google's Advanced function and contacted HIA practitioners via two international mailing lists. We used a bespoke quality appraisal tool to assess frameworks against the principles. RESULTS: The search identified 24 HIA frameworks. None of the frameworks achieved a 'good' rating for all best practice principles. Many identified the principles but did not provide guidance on how to meet them at all HIA steps. The highest number of frameworks were rated 'good' for ethical use of evidence and comprehensive approach to health (n = 15). Eight frameworks were rated as 'good' for participation, and two for equity. The highest number of frameworks rated 'poor' for sustainability (n = 11). CONCLUSIONS: There is marked variation in the degree to which HIA frameworks support the best practice principles. HIA practitioners could select elements from different frameworks for practical guidance to meet all the best practice principles.

Staged repair of borderline hypoplastic heart disease with early biventricular conversion.

Objective: In select patients with borderline ventricular hypoplasia, we adopted a strategy of initial single-ventricle palliation followed by staged or direct biventricular conversion by 2 years of age. Methods: Between 2018 and 2023, 14 newborns with borderline hypoplastic heart disease deemed high risk for primary biventricular repair underwent palliative procedures as a neonate/infant, followed by staged or direct biventricular conversion. Results: Of the 14 patients, 6 had borderline left ventricles and 8 had borderline right ventricles. Index neonatal operations were performed in 12 patients and included the Norwood operation (n = 5), pulmonary artery band (n = 3), ductal stent (n = 3), and hybrid Norwood (n = 1). Five patients underwent direct biventricular conversion, and the remaining 9 patients underwent staged ventricular recruitment operations at a mean age of 6 months (range, 3-11 months). Ventricular recruitment operations included atrial septation with or without ventricular rehabilitation, atrioventricular valve repair, or outflow tract operations. At a mean duration of 8 months (range, 4-10 months) after ventricular recruitment, there was a significant increase in chamber volume, aortic valve, and mitral valve size in patients with borderline left ventricles, and a normalization of the right ventricle:left ventricle end-diastolic volume ratio in patients with borderline right ventricles. To date, 13 of 14 patients have undergone successful biventricular conversion at a mean age of 16 months (range, 4-31 months). Conclusions: In select newborns with borderline hypoplastic heart disease, single-ventricle palliation followed by staged or direct biventricular conversion may increase infant survival while allowing for early attainment of a biventricular circulation.

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development.

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

The Past and Future of Angiogenesis as a Target for Cancer Therapy and Prevention.

Cancer growth is dependent on angiogenesis, the formation of new blood vessels, which represents a hallmark of cancer. After this concept was established in the 1970s, inhibition of tumor development and metastases by blocking the neoangiogenic process has been an important approach to the treatment of tumors. However, antiangiogenic therapies are often administered when cancer has already progressed. The key to reducing the cancer burden is prevention. We noticed 20 years ago that a series of possible cancer chemopreventive agents showed antiangiogenic properties when tested in experimental models. This article reviews the relevant advances in the understanding of the rationale for targeting angiogenesis for cancer therapy, prevention, and interception and recently investigated substances with antiangiogenic activity that may be suitable for such strategies. Many compounds, either dietary derivatives or repurposed drugs, with antiangiogenic activity are possible tools for cancer angioprevention. Such molecules have a favorable safety profile and are likely to allow the prolonged duration necessary for an efficient preventive strategy. Recent evidence on mechanisms and possible use is described here for food derivatives, including flavonoids, retinoids, triterpenoids, omega fatty acids, and carotenoids from marine microorganisms. As examples, a number of compounds, including epigallocatechin, resveratrol, xanthohumol, hydroxytyrosol, curcumin, fenretinide, lycopene, fucoxanthin, and repurposed drugs, such as aspirin, ß blockers, renin-angiotensin-aldosterone inhibitors, carnitines, and biguanides, are reviewed.

Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.

High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.

BACKGROUND: KCNE1 encodes a 129-residue cardiac potassium channel (IKs) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility. METHODS: In this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants. RESULTS: We comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56-104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ = - 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ = - 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants. CONCLUSIONS: Comprehensive variant effect maps of KCNE1 can both provide insight into I Ks channel biology and help reclassify variants of uncertain significance.

Measuring Quality of Life in Deprescribing Trials: A Scoping Review.

BACKGROUND: Quality of life (QoL) is an important outcome to capture in clinical trials evaluating deprescribing interventions. OBJECTIVE: We aimed to conduct a scoping review to examine how QoL has been measured in deprescribing trials among older people and identify potentially relevant QoL scales, to better inform QoL measurement in future deprescribing trials. METHODS: We searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, Google Scholar, Epistemonikos, ClinicalTrials.gov, and reference lists of eligible studies (from inception to October 2023). We included randomized and non-randomized comparative studies with a control group that evaluated deprescribing and polypharmacy reduction interventions in people ≥ 65 years of age and measured QoL as an outcome. We also included studies describing the development and validation of QoL scales related to deprescribing, polypharmacy, or medication burden in adults ≥ 18 years of age. Two independent reviewers screened titles and abstracts, then full texts. Two independent reviewers extracted data from 25% of eligible studies in order to verify agreement, then a single reviewer extracted data from the remaining studies, which a second reviewer cross-checked. We critically appraised scales based on the COSMIN checklist. RESULTS: We retrieved 7290 articles, of which 52 were eligible for inclusion, including 44 deprescribing trials and eight scale development studies. From these studies, we found 21 scales that have been used in the context of deprescribing/polypharmacy (12 generic scales used in clinical trials and nine medication-specific scales). Variations of the generic EQ-5D were the most used scales. The measurement properties of scales for capturing changes in QoL from deprescribing were uncertain. Medication-specific QoL scales have not been employed in deprescribing clinical trials and thus, their performance in this context is also not clear. CONCLUSIONS: Several existing QoL scales have been applied to the context of deprescribing/polypharmacy clinical trials, and new scales specific to the problem have been proposed. If deprescribing does impact QoL, our findings suggest it is uncertain whether existing QoL scales can practically and reliably capture such a change or whether any scale is best. However, this review compares various aspects of the scales that researchers and clinicians can consider in decisions about measuring QoL in deprescribing trials, and in planning future research. PROTOCOL REGISTRATION: Open Science Framework: osf.io/aez6w.