Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

Digital health and medical technology for perioperative sarcopenia optimisation and prehabilitation - Where to go from here?

Sarcopenia has been shown to cause poorer outcomes in surgical oncology. With the advancement of artificial intelligence technology, body composition analysis can be obtained with ease. Given the lead time between cancer diagnosis and surgery, selected patients at risk of complications secondary to sarcopenia may be amenable to prehabilitation. The COVID-19 pandemic has led to the rapid adaptation of digital health and medical technology. Our perspective piece will review the current available evidence and propose innovative ways to incorporate technology into physical and nutritional prehabilitation.

Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions.

Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR 4 ), which is expressed in sensory neurons of the peripheral nervous system, has emerged as a promising target for pain relief. However, the presence of several closely related receptors with similar ligand-binding surfaces complicates the design of receptor-specific agonists. In this study, we report the discovery of a potent and selective SSTR 4 peptide, consomatin Fj1, derived from extensive venom gene datasets from marine cone snails. Consomatin Fj1 is a mimetic of the endogenous hormone somatostatin and contains a minimized binding motif that provides stability and drives peptide selectivity. Peripheral administration of synthetic consomatin Fj1 provided analgesia in mouse models of postoperative and neuropathic pain. Using structure-activity studies, we designed and functionally evaluated several Fj1 analogs, resulting in compounds with improved potency and selectivity. Our findings present a novel avenue for addressing persistent pain through the design of venom-inspired SSTR 4 -selective pain therapeutics. One Sentence Summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.

Water and Air Stable Copper(I) Complexes of Tetracationic Catenane Ligands for Oxidative C-C Cross-Coupling.

Aqueous soluble and stable Cu(I) molecular catalysts featuring a catenane ligand composed of two dicationic, mutually repelling but mechanically interlocked macrocycles are reported. The ligand interlocking not only fine-tunes the coordination sphere and kinetically stabilizes the Cu(I) against air oxidation and disproportionation, but also buries the hydrophobic portions of the ligands and prevents their dissociation which are necessary for their good water solubility and a sustained activity. These catenane Cu(I) complexes can catalyze the oxidative C-C coupling of indoles and tetrahydroisoquinolines in water, using H2O2 as a green oxidant with a good substrate scope. The successful use of catenane ligands in exploiting aqueous Cu(I) catalysis thus highlights the many unexplored potential of mechanical bond as a design element for exploring transition metal catalysis under challenging conditions.

Dynamic mechanostereochemical switching of a co-conformationally flexible [2]catenane controlled by specific ionic guests.

Responsive synthetic receptors for adaptive recognition of different ionic guests in a competitive environment are valuable molecular tools for not only ion sensing and transport, but also the development of ion-responsive smart materials and related technologies. By virtue of the mechanical chelation and ability to undergo large-amplitude co-conformational changes, described herein is the discovery of a chameleon-like [2]catenane that selectively binds copper(I) or sulfate ions and its associated co-conformational mechanostereochemical switching. This work highlights not only the advantages and versatility of catenane as a molecular skeleton in receptor design, but also its potential in constructing complex responsive systems with multiple inputs and outputs.

Making Sense: Treating Patients with Opioid Use Disorder through the Lens of Game Theory.

The opioid epidemic continues to influence the field of medicine, creating new challenges and obstacles to quality care. Patients with injection drug use are marginalized individuals who received poor quality of care and often discharged without safe recovery plan. Cooperation between physicians and patients allow the best outcomes for the patient, the physician, and society, however we often see patient-directed discharges and inadequate care. We believe that this result is due to an incentive model in the decision-making process that ultimately makes cooperation difficult. We use different game theory models (assurance model, prisoner's dilemma, centipede model, conflicting interest coordination) in this paper to describe common scenarios within a hospitalization when caring for patient with opioid use disorder, from admission through discharge. When physician and patient are driven away from cooperation, the outcome is the worst and most harmful for society. In today's worsening opioid crisis, game theory can help physician provide high quality care to a complex high-risk population.

Quantitative Analysis of Characteristics Associated with Patient-Directed Discharges, Representations, and Readmissions: a Safety-Net Hospital Experience.

BACKGROUND: No clinical tools currently exist to stratify patients' risks of patient-directed discharge (PDD). OBJECTIVE: This study aims to identify trends and factors associated with PDD, representation, and readmission. DESIGN: This was an IRB-approved, single-centered, retrospective study. PARTICIPANTS: Patients aged > 18, admitted to medicine service, were included from January 1st through December 31st, 2019. Patients admitted to ICU or surgical services were excluded. MAIN MEASURES: Demographics, insurance information, medical history, social history, rates of events occurrences, and discharge disposition were obtained. KEY RESULTS: Of the 16,889 encounters, there were 776 (4.6%) PDDs, 4312 (25.5%) representations, and 2924 (17.3%) readmissions. Of those who completed PDDs, 42.1% represented and 26.4% were readmitted. Male sex, age ≤ 45, insurance type, homelessness, and substance use disorders had higher rates of PDD (OR = 2.0; 4.2; 4.5; 6.2; 5.2; p < 0.0001, respectively). Patients with homelessness, substance use disorders, mental health disorders, or prior history of PDD were more likely to represent (OR = 3.6; 2.0; 2.0; 1.5; p < 0.0001, respectively) and be readmitted (OR = 2.2; 1.6; 1.9; 1.5; p < 0.0001, respectively). Patients aged 30-35 had the highest PDD rate at 16%, but this was not associated with representations or readmissions. Between July and September, the PDD rate peaked at 5.5% and similarly representation and readmission rates followed. The rates of subsequent readmissions after PDDs were nearly two-fold compared to non-PDD patients in later half of the year. 51% of all subsequent readmissions occur within 7 days of PDD, compared to 34% in the non-PDD group (OR = 2.0; p < 0.0001). Patients with primary diagnosis of abscess had 16% PDDs. CONCLUSIONS: Factors associated with PDD include male, younger age, insurance type, substance use, homelessness, and primary diagnosis of abscess. Factors associated with representation and readmission are homelessness, substance use disorders, mental health disorders, and prior history of PDD. Further research is needed to develop a risk stratification tool to identify at-risk patients.

GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion.

AIMS/HYPOTHESIS: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. METHODS: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). RESULTS: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by ß-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca2+ entry via voltage-gated Ca2+ channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. CONCLUSIONS/INTERPRETATION: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.

Pyramid of Discharge Needs: A Simple Framework on Discharge Planning for Medical Students and Residents.

Medical students and residents often have difficulty with discharge planning and determining appropriate post-hospitalization level of care. As the discharge planning process can be complex, physicians in-training often do not engage until late into the hospitalization or near day of discharge. This paper offers a simple pyramid construct that categorizes common discharge needs into 4 areas or tiers. As the topic of discharge planning is not formally taught in medical education, most trainees learn through experience and by trial and error. Using a simple pyramid and a basic flow chart to guide students and residents, the discharge planning process can be introduced as soon as possible during the hospitalization.

Primary lung adenocarcinoma mimicking recurrent pneumonia in a young adult.

A man in his 20s with a history of tobacco use presented with recurrent shortness of breath. He was hospitalised three times within the past 4 months for similar symptoms despite completing several courses of antibiotic therapy. In this presentation, he was afebrile with rhonchi and decreased breath sounds over the right lung. Chest CT demonstrated large consolidations in the right middle and lower lobes, worsened compared with 4 months prior. Infectious workup including bronchoscopy with bronchoalveolar lavage did not identify a causative organism. Testing for immune disease was negative. Transbronchial biopsy ultimately identified well-differentiated stage 3b lung adenocarcinoma with a KRAS G12C mutation. The patient was referred to oncology for outpatient follow-up and has since initiated chemotherapy. This case highlights diagnostic biases encountered in young patients and the utility of bronchoscopic biopsy for definitive diagnosis in presumed community-acquired pneumonia when the clinical outcome is not improving as expected.

Catenane and Rotaxane Synthesis from Cucurbit[6]uril-Mediated Azide-Alkyne Cycloaddition.

The chemistry of mechanically interlocked molecules (MIMs) such as catenane and rotaxane is full of new opportunities for the presence of a mechanical bond, and the efficient synthesis of these molecules is therefore of fundamental importance in realizing their unique properties and functions. While many different types of preorganizing interactions and covalent bond formation strategies have been exploited in MIMs synthesis, the use of cucurbit[6]uril (CB[6]) in simultaneously templating macrocycle interlocking and catalyzing the covalent formation of the interlocked components is particularly advantageous in accessing high-order catenanes and rotaxanes. In this review, catenane and rotaxane obtained from CB[6]-catalyzed azide-alkyne cycloaddition will be discussed, with special emphasis on the synthetic strategies employed for obtaining complex [n]rotaxanes and [n]catenanes, as well as their properties and functions.

The risk factors, consequences, and interventions of discharge against medical advice - A narrative review.

Discharge against medical advice (DAMA) represents an increasingly burdensome public health issue that leads to worse outcomes for patients and high costs to society. While the rate of patients who DAMA is higher within certain institutions and geographic locations, the problem is present across all healthcare systems. DAMAs are often challenging as they occur suddenly and can be unsatisfactory. An opportunity exists to better meet the needs of this patient population; however, many providers are unsure of how they can prevent a DAMA. In this review, we discuss the broader impact, associated factors, the most common reasons, the consequences, and the prevention strategies for DAMA. Further research is needed to create tools for stratifying patients most likely to DAMA. Early identification and appropriate interventions for these patients will allow for safe discharges.

Mechanical Interlocking Enhances the Electrocatalytic Oxygen Reduction Activity and Selectivity of Molecular Copper Complexes.

Efficient O2 reduction reaction (ORR) for selective H2O generation enables advanced fuel cell technology. Nonprecious metal catalysts are viable and attractive alternatives to state-of-the-art Pt-based materials that are expensive. Cu complexes inspired by Cu-containing O2 reduction enzymes in nature are yet to reach their desired ORR catalytic performance. Here, the concept of mechanical interlocking is introduced to the ligand architecture to enforce dynamic spatial restriction on the Cu coordination site. Interlocked catenane ligands could govern O2 binding mode, promote electron transfer, and facilitate product elimination. Our results show that ligand interlocking as a catenane steers the ORR selectivity to H2O as the major product via the 4e- pathway, rivaling the selectivity of Pt, and boosts the onset potential by 130 mV, the mass activity by 1.8 times, and the turnover frequency by 1.5 fold as compared to the noninterlocked counterpart. Our Cu catenane complex represents one of the first examples to take advantage of mechanical interlocking to afford electrocatalysts with enhanced activity and selectivity. The mechanistic insights gained through this integrated experimental and theoretical study are envisioned to be valuable not just to the area of ORR energy catalysis but also with broad implications on interlocked metal complexes that are of critical importance to the general fields in redox reactions involving proton-coupled electron transfer steps.

Applying Game Theory Models to Inpatient Medicine: Opportunities to Improve Care.

Inpatient hospital costs have been increasing exponentially in the United States. Part of this increase is attributed to over and undertreatment, leading to higher costs and potential patient harm. Research improving clinician-patient interactions can help minimize and optimize the costs. Game theory has the ability improve clinician-patient interaction by modeling outcomes. Using variations of game theory, the bad doctor bad patient stigma can reframed to incentives. We believe the use of different models (prisoner dilemma, centipede game, assurance game, and chicken game) can outline the challenges faced during common inpatient scenarios, including end of life conversations and aggressive procedures. Applying game theory to multiple inpatient scenarios may also assist with analysis during morbidity and mortality conferences and quality improvement projects.

Design of Nickel Supported Hierarchical ZSM-5/USY Zeolite Bifunctional Catalysts for One-Pot Menthol Synthesis via Liquid-Phase Citral Hydrogenation.

Nickel-supported hierarchical zeolite catalysts were prepared through a desilication reassembly process under optimized conditions and applied in one-pot menthol synthesis. In this work, the hierarchical zeolite-supported metal bifunctional catalysts were prepared with the help of desilication re-assembly and wetness impregnation techniques and applied in menthol synthesis via citral hydrogenation. The prepared catalysts were characterized using PXRD, BET, FE-TEM, NH3-TPD, H2-TPR, pyridine adsorption, and ICP-OES techniques. As a result, the physicochemical and acidic properties, such as mesopore surface area, metal dispersion, acidity, catalytic activity, and strong Lewis acid sites of pure microporous ZSM-5/USY zeolites, were significantly improved. Consequently, with the occurrence of superior physicochemical and acidic properties, the Ni/HZ-0.5 M catalyst exhibited outstanding catalytic activity (100% conversion, TOF 7.12 h-1) and menthol selectivity (83%, 4 h) with uniform stability at 100 °C, 1.0 MPa hydrogen. Similarly, the cracking rate decreased with the decrease in Bronsted acid sites.

Comparative Outcomes of Second-line Topoisomerase-I Inhibitor Therapies on Neuroendocrine Carcinoma.

INTRODUCTION: This investigation aims to assess the outcomes for second-line therapies to treat extrapulmonary neuroendocrine carcinoma (EP-NEC) after first-line platinum-based chemotherapy. METHODS: With IRB approval, we conducted a retrospective study of EP-NEC patients that progressed on first-line platinum chemotherapy from 2008 to 2018. Demographic data and treatment-related characteristics were collected and represented as descriptive statistics. The primary endpoints include overall survival (OS) and progression-free survival (PFS). OS and PFS were estimated and stratified by site of primary (gastroenteropancreatic [GEP] versus non-GEP) and type of second-line therapy (irino/topotecan versus others). Log-rank test and Kaplan-Meier curves were used to compare survival distributions between groups. RESULTS: Forty-seven patients met eligibility, with median age 65 (range 31-82), 62% male, and 83% White; 22 were GEP and 25 were non-GEP primary. Thirty patients (63.8%) received second-line therapy where 11 received irinotecan/topotecan (ir/to), while 19 received other agents (temozolomide, other platinum agents, gemcitabine, paclitaxel, pembrolizumab, and sunitinib). The median OS was 10.3 months in the ir/to group versus 13.4 months for other therapies, p = 0.10. The median PFS for ir/to therapy compared to other therapies was 2.0 months versus 1.8 months, respectively, p = 0.72. The OS and PFS with and without ir/to were not significantly different by the primary site (p = 0.61 and p = 0.21). DISCUSSION/CONCLUSION: Many EP-NEC patients undergo second-line therapies. Interestingly, outcomes for ir/to-containing second-line therapies were not statistically different from other agents, regardless of the site of primary. With approval of new second-line therapies for small cell lung cancer, further research in therapeutic options is needed for this aggressive disease.

Development of Fluorescent Turn-On Probes for CAG-RNA Repeats.

Fluorescent sensing of nucleic acids is a highly sensitive and efficient bioanalytical method for their study in cellular processes, detection and diagnosis in related diseases. However, the design of small molecule fluorescent probes for the selective binding and detection of RNA of a specific sequence is very challenging because of their diverse, dynamic, and flexible structures. By modifying a bis(amidinium)-based small molecular binder that is known to selectively target RNA with CAG repeats using an environment-sensitive fluorophore, a turn-on fluorescent probe featuring aggregation-induced emission (AIE) is successfully developed in this proof-of-concept study. The probe (DB-TPE) exhibits a strong, 19-fold fluorescence enhancement upon binding to a short CAG RNA, and the binding and fluorescence response was found to be specific to the overall RNA secondary structure with A·A mismatches. These promising analytical performances suggest that the probe could be applied in pathological studies, disease progression monitoring, as well as diagnosis of related neurodegenerative diseases due to expanded CAG RNA repeats.

Basilar Predominant Emphysema: Thinking beyond Alpha-1-Antitrypsin Deficiency.

Basilar predominant emphysema, or disproportionate emphysematous involvement of the lung bases compared to the apices, is an uncommon radiographic pattern of emphysema traditionally associated with alpha-1-antitrypsin deficiency (AATD). We present a case of a 59-year-old female with 41 pack-year tobacco use, Stage IV COPD with supplemental oxygen, and bibasilar predominant emphysema who successfully underwent bronchoscopic lung volume reduction. She presented with recurrent hospitalizations for frequent exacerbations. After lung reduction, the patient displayed improvement in functional status without hospitalizations at the 15-month follow-up. Careful history taking is essential for any patients diagnosed with lower lobe emphysema to elucidate the underlying etiology. This case challenges the notion that basilar emphysema is sensitive or specific for AATD and emphasizes that this pattern of emphysema has a broad differential diagnosis and alternative etiologies should be considered. Our patient was ultimately diagnosed with smoking-related emphysema, with atypical bibasilar involvement. Furthermore, basilar predominant emphysema should be considered a separate entity from its apical predominant counterpart.