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Background: Management of esophageal perforation includes open surgery, minimally invasive surgery, and endoscopic stent placement. This study analyzed initial treatment and the associated short-term outcomes., Methods: A retrospective study using the National Inpatient Sample between October 2015 and December 2019 identified adults >18 years with esophageal perforation undergoing an initial nonelective esophageal procedure categorized into either open surgery, minimally invasive surgery, or endoscopic stent placement. Patients with esophageal cancer were excluded. Baseline characteristics and the van Walraven-weighted Elixhauser Comorbidity Index were identified. Outcomes included in-hospital mortality and postintervention complications. Univariable and multivariable Cox regression was used to compare in-hospital survival., Results: In total, 3,345 patients met inclusion criteria: the median age was 62 years (interquartile range 50-72 years), and 1,310 (39%) were female. Open procedure was pursued in 2,650 (79%), minimally invasive surgery in 310 (9%), and endoscopic stent placement in 385 (12%) with no differences in van Walraven-weighted Elixhauser Comorbidity Index or mortality. Patients who underwent minimally invasive surgery had a greater proportion of gastrointestinal complications (P = .006); otherwise, there were no differences in postintervention complications. In total, 380 (11%) patients died and were significantly older, with greater van Walraven-weighted Elixhauser Comorbidity Index, and had more postintervention complications. Univariable Cox regression identified age (hazard ratio 1.95, P < .001), van Walraven-weighted Elixhauser Comorbidity Index (hazard ratio 1.06, P < .001), stent placement (hazard ratio 1.93, P = .045), and transfer from a health facility (HR 2.40, P = .049) as associated with decreased in-hospital survival. Multivariable Cox regression revealed age (hazard ratio 1.041, P < .001) and van Walraven-weighted Elixhauser comorbidity index (hazard ratio 1.055, P < .001) were associated with decreased in-hospital survival., Conclusion: Patients with esophageal perforation had an 11% in-hospital mortality rate and significant associated complications regardless of intervention. Increasing age and comorbidities are associated with poorer in-hospital survival., (Published by Elsevier Inc.)

Objective: To compare outcomes of single-lung retransplantation (SLRTx) and double-lung retransplantation (DLRTx) after an initial double-lung transplantation., Methods: The Organ Procurement and Transplantation Network/United Network for Organ Sharing database between May 2005 and December 2022 was retrospectively analyzed. Multiorgan transplantations, repeated retransplantations, and lung retransplantations when the status of the initial transplantation was unknown were excluded., Results: A total of 891 patients were included in the analysis, included 698 (78.3%) with DLRTx and 193 (21.7%) with SLRTx. The mean lung allocation score was higher in the DLRTx group (59.6 ± 20.7 vs 55.1 ± 19.3; P = .007). The use of extracorporeal membrane oxygenation (ECMO) bridge to lung transplantation was similar in the 2 groups (P = .125), as was waitlist time (P = .610). The need for mechanical ventilation (54.6% vs 35.8%; P = .005) and ECMO (17.9% vs 9.0%; P = .069) at 72 hours post-transplantation was greater in the DLRTx group. However, median post-transplantation hospital stay (21.5 [interquartile range (IQR), 12-35] days versus 20 [IQR, 12-35] days; P = .119) and in-hospital mortality (10.9% [n = 76/698] vs 12.4% [n = 24/193]; P = .547) were comparable in the 2 groups. Long-term survival was significantly better in the DLRTx group (P < .001, log-rank test). In the propensity score-weighted multivariable model, the DLRTx group had 28% lower risk of mortality at any point during follow-up compared to the SLRTx group (hazard ratio, 0.72; 95% confidence interval, 0.57-0.91; P = .006)., Conclusions: The less invasiveness of single-lung transplantation in the retransplantation setting has minimal short-term benefit and is associated with significantly worse long-term survival. Double-lung retransplantation should remain the standard for lung retransplantation after initial double-lung transplantation., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Treatment for venous thoracic outlet syndrome (vTOS) includes thrombolysis followed by decompressive rib resection. Given the rarity of the disease, the goal of this study was to describe current practices in treatment of vTOS., Methods: All patients with diagnoses of subclavian vTOS who underwent rib resection in the 2018-2020 Nationwide Readmissions Database were included in this study. Patients were grouped based on number of days between thrombolysis and by number of hospitalizations: thrombolysis followed by surgery in the same hospitalization was considered "simultaneous" and in separate hospitalizations was "staged.", Results: Five hundred ninety patients met the inclusion criteria. The average age was 34.1 ± 13.3 y, and 42.9% (253 of 590) were female. Among the patients receiving thrombolysis and decompressive rib resection, 46.8% (164 of 350) patients had <14 d between interventions, 19.1% (67 of 350) patients had 14-30 d between interventions, and 34.0% (119 of 350) had >30 d between interventions. There were no significant differences in postoperative bleeding between patients with <14 d, 14-30 d, and >30 d between thrombolysis and surgery. In terms of number of hospital visits, 19.0% (112 of 590) had "simultaneous" thrombolysis and surgery and 40.5% (239 of 590) had thrombolysis and surgery in a "staged" approach. Forty point five percent (239 of 590) of patients received only surgical decompression without thrombolysis., Conclusions: Thrombolysis followed by first rib resection for vTOS can be performed during the same hospital admission without an associated risk of bleeding complications., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: Patients undergoing re-transplantation constitute a growing proportion of annual lung transplants. It is necessary to consider ethical considerations of re-transplantation in parallel with clinical progress., Recent Findings: Most clinical data demonstrate patients undergoing re-transplantation have worse survival outcomes; however, there is limited discussion of the ethical principles surrounding re-transplantation. Ethical guidance in re-transplantation trails clinical advancement., Summary: The four-box model offers a valuable framework for assessing the ethical considerations in re-transplantation. This includes an analysis of medical indications, patient preferences, quality-of-life and contextual factors to support the ethical use of scarce donor lungs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into pathogenic amyloid fibrils. One protein so identified was the tropomyosin-receptor kinase-fused gene protein (TRK-fused gene protein or TFG). Mutations in TFG are associated with degenerative neurological conditions. Here, we present experimental evidence that confirms our prediction that these conditions are amyloid-related. We find that the low-complexity domain of TFG containing the disease-related mutations G269V or P285L forms amyloid fibrils, and we determine their structures using cryo-electron microscopy (cryo-EM). These structures are unmistakably amyloid in nature and confirm the propensity of the mutant TFG low-complexity domain to form amyloid fibrils. Also, despite resulting from a pathogenic mutation, the fibril structures bear some similarities to other amyloid structures that are thought to be nonpathogenic and even functional, but there are other factors that support these structures' relevance to disease, including an increased propensity to form amyloid compared with the wild-type sequence, structure-stabilizing influence from the mutant residues themselves, and double-protofilament amyloid cores. Our findings elucidate two potentially disease-relevant structures of a previously unknown amyloid and also show how the structural features of pathogenic amyloid fibrils may not conform to the features commonly associated with pathogenicity., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP's propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development., (© 2023. The Author(s).)

The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans . Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

Low-complexity domains (LCDs) of proteins have been shown to self-associate, and pathogenic mutations within these domains often drive the proteins into amyloid aggregation associated with disease. These domains may be especially susceptible to amyloidogenic mutations because they are commonly intrinsically disordered and function in self-association. The question therefore arises whether a search for pathogenic mutations in LCDs of the human proteome can lead to identification of other proteins associated with amyloid disease. Here, we take a computational approach to identify documented pathogenic mutations within LCDs that may favor amyloid formation. Using this approach, we identify numerous known amyloidogenic mutations, including several such mutations within proteins previously unidentified as amyloidogenic. Among the latter group, we focus on two mutations within the TRK-fused gene protein (TFG), known to play roles in protein secretion and innate immunity, which are associated with two different peripheral neuropathies. We show that both mutations increase the propensity of TFG to form amyloid fibrils. We therefore conclude that TFG is a novel amyloid protein and propose that the diseases associated with its mutant forms may be amyloidoses., Competing Interests: Conflict of interest D. S. E. is SAB Chair and equity holder in ADRx, Inc. All the other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022. Published by Elsevier Inc.)

Background: Monitoring longitudinal patient-reported outcomes after injury is important for comprehensive trauma care. Current methodologies are resource-intensive and struggle to engage patients., Materials and Methods: Patients ≥18 y old admitted to the trauma service were prospectively enrolled. The following inclusion criteria were used: emergency operation, ICU length of stay ≥2 midnights, or hospital length of stay ≥4 d. Validated and customized questionnaires were administered using a novel internet-based survey platform. Three-month follow-up surveys were administered. Contextual field notes regarding barriers to enrollment/completion of surveys and challenges faced by participants were recorded., Results: Forty-seven patients were eligible; 26 of 47 (55%) enrolled and 19 of 26 (73%) completed initial surveys. The final sample included 14 (74%) men and 5 (26%) women. Primary barriers to enrollment included technological constraints and declined participation. Contextual field notes revealed three major issues: competing hospital tasks, problems with technology, and poor engagement. The average survey completion time was 43 ± 27 min-21% found this too long. Seventy-four percent reported the system "easy to use" and 95% reported they would "very likely" or "definitely" respond to future surveys. However, 10 of 26 (38%) patients completed 3-mo follow-up., Conclusions: Despite a well-rated internet-based survey platform, study participation remained challenging. Lack of email access and technological issues decreased enrollment and the busy hospitalization posed barriers to completion. Despite a thoughtful operational design and implementation plan, the trauma population presented a challenging group to engage. Next steps will focus on optimizing engagement, broadening access to survey reminders, and enhancing integration into clinical workflows., (Copyright © 2019 Elsevier Inc. All rights reserved.)

More people are surviving traumatic injury, but disability and reduced quality of life are frequent. Investigators are now focusing on patient-reported outcomes (PROs) to better understand this problem. We performed a scoping study of the literature to explore trends in the study of PROs after injury. The volume of published literature on PROs after injury has consistently increased, but use of measurement tool and categorization of publications are inconsistent. Journal keyword patterns are inconsistent and likely limit the effective dissemination of important findings. In studies of hospitalized trauma patients, more than 100 unique measurement tools were used, and trauma-specific measures were used in fewer than 5% of studies. International investigators are more consistent than those in the USAin the use of validated, classic measurement tools such as the Short-Form 36 and the EuroQoL Five-Dimension tools. Uniform use of measurement tools would help improve the quality and comparability of research on PROs, and trauma-specific measures would enhance the study of long-term injury outcomes., Competing Interests: Competing interests: None declared.

Background: Recent data suggest improved splenic salvage rates when angioembolization (AE) is routinely employed for high-grade splenic injuries; however, protocols and salvage rates vary among centers., Materials/methods: Adult patients with isolated splenic injuries were identified using the National Trauma Data Bank, 2013-2014. Patients were excluded if they underwent immediate splenectomy or died in the emergency department. To characterize patterns of AE, trauma centers were grouped into quartiles based on frequency of AE use. Unadjusted analyses and mixed-effects logistical regression controlling for center effects were performed., Results: Five thousand and ninety three adult patients were identified. Overall, 705 (13.8%) underwent AE and 290 (5.7%) required a splenectomy. In unadjusted comparisons, splenectomy rates were lower for patients with severe spleen injuries who underwent AE (7% versus 11%, P = 0.02). In mixed-effect logistical regression patients with severe splenic injuries undergoing AE had a lower odds ratio (OR) for splenectomy (OR = 0.67, P = 0.04). Patients treated at centers in the highest quartile of AE use had a lower OR for splenectomy (OR = 0.58, P = 0.02)., Conclusions: The use of AE in patients with isolated severe splenic injuries is associated with decreased splenectomy rates. There is an association between centers that perform AE frequently and reduced splenectomy rates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Options for managing splenic injuries have evolved with a focus on nonoperative management. Long-term outcomes, such as readmissions and delayed splenectomy rate, are not well understood., Objective: To describe the natural history of isolated splenic injuries in the United States and determine whether patterns of readmission were influenced by management strategy., Design, Setting, and Participants: The Healthcare Cost and Utilization Project's Nationwide Readmission Database is an all-payer, all-ages, longitudinal administrative database that provides data on more than 35 million weighted US discharges yearly. The database was used to identify patients with isolated splenic injuries and the procedures that they received. Adult patients with isolated splenic injuries admitted from January 1 through June 30, 2013, and from January 1 through June 30, 2014, were included. Those who died during the index hospitalization or who had an additional nonsplenic injury with an Abbreviated Injury Score of 2 or greater were excluded. Univariate and mixed-effects logistic regression analysis controlling for center effect were used. Weighted numbers are reported., Exposures: Initial management strategy at the time of index hospitalization, including nonprocedural management, angioembolization, and splenectomy., Main Outcomes and Measures: All-cause 6-month readmission rate. Secondary outcome was delayed splenectomy rate., Results: A weighted sample of 3792 patients (2146 men [56.6%] and 1646 women [43.4%]; mean [SE] age, 48.5 [0.7] years) with 5155 admission events was included. During the index hospitalization, 825 (21.8%) underwent splenectomy, 293 (7.7%) underwent angioembolization, and 2673 (70.5%) had no procedure. The overall readmission rate was 21.1% (799 patients). Readmission rates did not differ based on initial management strategy (195 patients undergoing splenectomy [23.6%], 70 undergoing angioembolism [23.9%], and 534 undergoing no procedure [20%]; P = .33). Splenectomy was performed in 36 of 799 readmitted patients (4.5%) who did not have a splenectomy at their index hospitalization, leading to an overall delayed splenectomy rate of 1.2% (36 of 2967 patients). In mixed-effects logistic regression analysis controlling for patient, injury, clinical, and hospital characteristics, the choice of splenectomy (odds ratio, 0.93; 95% CI, 0.66-1.31) vs angioembolization (odds ratio, 1.19; 95% CI, 0.72-1.97) as initial management strategy was not associated with readmission., Conclusions and Relevance: This national evaluation of the natural history of isolated splenic injuries from index admission through 6 months found that approximately 1 in 5 patients are readmitted within 6 months of discharge after an isolated splenic injury. However, the chance of readmission for splenectomy after initial nonoperative management was 1.2%. This finding suggests that the current management strategies used for isolated splenic injuries in the United States are well matched to patient need.

Twenty-eight nonconstrained capitellocondylar elbow offhroplasties were performed in 23 patients. The clinical criteria were intractable pain in a joint with radiologic destruction from rheumatoid arthritis. Patients were examined at an average of 35 months postsurgery with the Ewald scoring system. Results were satisfactory in 24 elbows (86%) and unsatisfactory in four (14%). Pain relief and functional improvement were dramatic. The average arc of motion increased from 88 degrees preoperation to 101 degrees postoperation. There was an average 33 degrees residual flexion contracture. There was one failure from loosening, but no radiographic or clinical loosening was detected in the remaining patients. Postoperative dislocation was the most frequent complication, occurring in four cases. One dislocation required revision while three stabilized following four weeks of immobilization. There were two remote infections occurring two and five years postoperation. Although complications are frequent, this is a predictably successful procedure in properly selected patients.

Because published data on the effect of normal aging on serum calcium and phosphate levels are scanty and contradictory, we measured these parameters in 36 normal women over the age of 65 and compared these values with those obtained previously and concurrently in younger women. We found a significant decline in both serum calcium and phosphate levels after the age of 65. We also measured corrected total serum calcium, serum ultrafiltrable calcium, and serum ionized calcium levels in all of the elderly women and in 29 of the younger women and concluded that the decline in total serum calcium levels seen with aging was attributable in part to decreased levels of protein bound calcium but that there was also a slight reduction of ionic calcium levels. Data obtained in elderly women with proven parathyroid adenomas are included to illustrate how the recognition of these age related changes in total serum calcium levels may aid in the identification of slight but clinically important hypercalcemia in elderly adults.

The examination of an elderly patient often requires special techniques and attention to the patient's comfort and ease. This paper outlines a reasonable approach to each phase of the interview and discusses the particular medical problems of this age group. Older people are often slow to bring their troubles to medical attention because their symptoms are vague or because they accept their disability as part of old age. Sometimes they have difficulty in communicating effectively with the physician. Simple patience can ease an otherwise frustrating situation.

Total elbow arthroplasty (TEA) was used as a salvage procedure following failed open reduction and internation fixation, failed triaxial arthroplasties, and septic and aseptic loosening of implant arthroplasty. A minimally constrained bicondylar implant with a block to disarticulation was substituted for the reconstruction of 20 revision TEAs. Custom-designed implant TEA was substituted in cases with substantial bony or soft tissue loss. Revision of the polyethylene-bearing component, coupled with the addition of a yolk-type locking mechanism, was implanted when only the bearing system of a well-fixed implant had failed. TEA can be performed successfully with satisfactory durability as a revision procedure. Revision of failed open reduction internal fixation or a failed bearing system was highly successful. Revision of previously infected elbows in a single-stage procedure was unsuccessful in two of three cases and has been abandoned in favor of a staged procedure. A revision of loose TEA was successful in only three of five cases. Further investigations are necessary to improve the function durability of TEA.

Calculous gallbladder disease is the most common indication for intra-abdominal surgery in the elderly. Feeding bile salts may possibly increase the solubility of cholesterol in bile and may cause diminution in the size of radiolucent gallstones, the principal ingredient of which is cholesterol. However, indications for such treatment are still not clear, and long-term effectiveness and safety still have to be evaluated. If the aged patient with gallstones has severe symptoms, is a good medical risk and is not demented, surgical treatment should not be denied because of advanced age. If the patient has "silent" or "dyspeptic" gallstones and is a poor risk or demented, surgical therapy should be postponed at least temporarily, in the hope that medical methods for dissolving gallstones soon will be perfected.