Same-Day Home Recovery for Benign Foregut Surgery.

Importance: Same-day home recovery (SHR) is now the standard of care for many major surgical procedures and has the potential to become standard practice for benign foregut procedures (eg, hiatal hernia repair, fundoplication, and Heller myotomy). Objective: To determine whether SHR for patients undergoing benign foregut surgery is feasible, safe, and effective. Design, Setting, and Participants: This prospective cohort study took place across 19 medical centers within an integrated health care system in northern California from January 2019 through September 2021. Participants included consecutive patients undergoing elective benign foregut surgery. Exposures: Standardized SHR program. Main Outcomes and Measures: The primary end point was the rate of SHR. The secondary end points were 7-day and 30-day rates of postoperative emergency department visits, hospital readmissions, and reoperations. Results: Of 1248 patients who underwent benign foregut surgery from January 2017 through September 2021, 558 were patients before implementation of the SHR program and 690 were patients postimplementation. The mean age of patients was 60 years, and 759 (59%) were female. The preimplementation SHR rate was 64 of 558 patients (11.5%) in 2018 and increased to 82 of 113 patients (72.6%) by 2021 (94/350 [26.9%] in 2019 and 112/227 [49.3%] in 2020; P < .001). There were no statistical differences in the 7-day and 30-day rates of postoperative emergency visits, hospital readmissions, and reoperations or 30-day mortality in the SHR vs non-SHR groups in the postimplementation era. Conclusions and Relevance: In this study, implementation of a regional SHR program among patients undergoing elective benign foregut surgery was feasible, safe, and effective. The changes in perioperative care require comprehensive patient education and full multidisciplinary support. An SHR program for benign foregut procedures has the potential to improve patient care and cost-effectiveness in care delivery.

α-synuclein-assisted oligomerization of ß-amyloid (1-42).

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders, characterized by aggregation of amyloid polypeptides, ß-amyloid (Aß) and α-synuclein (αS), respectively. Aß and αS follow similar aggregation pathways, starting from monomers, to soluble toxic oligomeric assemblies, and to insoluble fibrils. Various studies have suggested overlaps in the pathologies of AD and PD, and have shown Aß-αS interactions. Unfortunately, whether these protein-protein interactions lead to self- and co-assembly of Aß and αS into oligomers - a potentially toxic synergistic mechanism - is poorly understood. Among the various Aß isoforms, interactions of Aß containing 42 amino acids (Aß (1-42), referred to as Aß42) with αS are of most direct relevance due to the high aggregation propensity and the strong toxic effect of this Aß isoform. In this study, we carefully determined molecular consequences of interactions between Aß42 and αS in their respective monomeric, oligomeric, and fibrillar forms using a comprehensive set of experimental tools. We show that the three αS conformers, namely, monomers, oligomers and fibrils interfered with fibrillization of Aß42. Specifically, αS monomers and oligomers promoted oligomerization and stabilization of soluble Aß42, possibly via direct binding or co-assembly, while αS fibrils hindered soluble Aß42 species from converting into insoluble aggregates by the formation of large oligomers. We also provide evidence that the interactions with αS were mediated by various parts of Aß42, depending on Aß42 and αS conformers. Furthermore, we compared similarities and dissimilarities between Aß42-αS and Aß40-αS interactions. Overall, the present study provides a comprehensive depiction of the molecular interplay between Aß42 and αS, providing insight into its synergistic toxic mechanism.

MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.

Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1ß from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.

Characteristics of Methamphetamine-associated Cardiomyopathy and the Impact of Methamphetamine Use on Cardiac Dysfunction.

Methamphetamine-associated cardiomyopathy (MACM) in an increasingly prevalent disease yet presenting clinical characteristics have not been well studied. We studied consecutive patients with MACM presenting between June 2018 and March 2020 who were interviewed for drug use and medical history. We retrospectively identified an age- and gender-matched cohort of Non-MACM (NMACM) patients and compared clinical characteristics. 140 patients (70 MACM and 70 NMACM) were studied. MACM patients were young (49.6 ± 10 years) and predominantly male (94%). Compared to NMACM, MACM patients were more likely to be Caucasian (21% vs 6%, p = 0.007) and homeless (47% vs 7%, p = 0.001). MACM was characterized by lower left ventricular ejection fraction (EF) (p <0.001) and greater LV end diastolic volume (LVEDV) (p = 0.024). Right ventricular (RV) dilation was present more often (p = s0.001) and was more often severe (p = 0.03). Among MACM cases, half of the cohort developed MACM within 5 years of starting MA (18% within 1 year). There was no apparent relationship between frequency or amount of MA used weekly with time until heart failure onset. Drug use patterns were not clearly related to the degree of LV structural change however there were more consistent, significant associations with RV and right atrial (RA) size parameters. In conclusion, patients with MACM have more severe myocardial impairment with lower EF, greater LVEDV and RV dilation. Drug use patterns do not clearly impact degree of LV structural changes by echocardiography however may be related to RV and RA size.

The incidence and risk factors for venous thromboembolism in adolescent and young adult oncology patients.

BACKGROUND: Venous thromboembolism (VTE) is a known complication among pediatric and adult cancer patients. Adolescent and young adult oncology (AYAO) patients have unique biological and physiological characteristics that make them distinct from other populations. Our objective was to study the VTE incidence, risk factors, and outcomes, which have been understudied in this population. PROCEDURE: A retrospective case-control study was conducted on AYAO participants with new or relapsed cancer and an imaging confirmed VTE from January 2011 to November 2016 at our institution. Eligible AYAO participants without a history of VTE were designated as controls and were randomly selected from our institution's tumor registry. Demographics, medical history, surgeries, central venous catheter (CVC) data, VTE diagnosis and treatment, relapses, and deaths were abstracted. RESULTS: Thirty-five VTE cases and 70 controls were included in this analysis. Eighty percent of cases had leukemia or lymphoma (vs. a solid tumor) compared to 58% of controls. The majority of VTEs (57%) were CVC associated, and more than 70% of cases had more than one CVC placed during their cancer treatment versus 34% of controls. Infection was associated with increased VTE risk (OR = 6.35, 95% CI = 2.30, 17.55, p < .0001). VTE cases had increased cancer relapse (23% vs. 10%) and mortality rates (29% vs. 16%) than controls. CONCLUSION: AYAO participants with a VTE were more likely to have leukemia or lymphoma, more than one CVC or infection. Further studies are needed to identify patients who would benefit from modifiable prevention measures, such as limiting to one CVC, preventing infections, or considering prophylactic anticoagulation for those with a liquid tumor.

A KLVFFAE-Derived Peptide Probe for Detection of Alpha-Synuclein Fibrils.

Aggregation of an amyloid protein, α-synuclein (αS), is a critical step in the neurodegenerative pathway of Parkinson's diseases (PD). Specific detection of amyloid conformers (i.e., monomers, oligomers, and fibrils) produced during αS aggregation is critical in better understanding a molecular basis of PD and developing a diagnostic tool. While various molecular probes are available for detection of αS fibrils, which may serve as a reservoir of toxic αS aggregate forms, these probes suffer from limited conformer-specificity and operational flexibility. In the present study, we explored the potential of non-self-aggregating peptides derived from the highly aggregation-prone KLVFFAE region of an amyloid protein, ß-amyloid, as molecular probes for αS aggregates. We show that of the four peptides tested (KLVFWAK, ELVFWAE, and their C-terminal capping variants, all of which were attached with fluorescein isothiocyanate at their respective N-termini), KLVFWAK with C-terminal capping was selectively bound to αS fibrils over monomers and oligomers and readily used for monitoring αS fibrilization. Our analyses suggest that binding of the peptide to αS fibrils is mediated by both electrostatic and hydrophobic interactions. We anticipate that our peptide can readily be optimized for conformer-specificity and operational flexibility. Overall, this study presents the creation of a KLVFFAE-based molecular probe for αS fibrils and demonstrates fine-tuning of its conformer-specificity by terminal mutations and capping.

Interactions between Soluble Species of ß-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization.

Aggregations of ß-amyloid (Aß) and α-synuclein (αS) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although Aß and αS affect different regions of the brain and are separated at the cellular level, there is evidence of their eventual interaction in the pathology of both disorders. Characterization of interactions of Aß and αS at various stages of their aggregation pathways could reveal mechanisms and therapeutic targets for the prevention and cure of these neurodegenerative diseases. In this study, we comprehensively examined the interactions and their molecular manifestations using an array of characterization tools. We show for the first time that αS monomers and oligomers, but not αS fibrils, inhibit Aß fibrillization while promoting oligomerization of Aß monomers and stabilizing preformed Aß oligomers via coassembly, as judged by Thioflavin T fluorescence, transmission electron microscopy, and SDS- and native-PAGE with fluorescently labeled peptides/proteins. In contrast, soluble Aß species, such as monomers and oligomers, aggregate into fibrils, when incubated alone under the otherwise same condition. Our study provides evidence that the interactions with αS soluble species, responsible for the effects, are mediated primarily by the C-terminus of Aß, when judged by competitive immunoassays using antibodies recognizing various fragments of Aß. We also show that the C-terminus of Aß is a primary site for its interaction with αS fibrils. Collectively, these data demonstrate aggregation state-specific interactions between αS and Aß and offer insight into a molecular basis of synergistic biological effects between the two polypeptides.

A rare systemic etiology of heart failure and liver dysfunction.

Systemic amyloidosis is a rare condition that can manifest with cardiomyopathy, hepatic dysfunction, and renal disease. Diagnosis is often missed and/or delayed due to chronic multi-system involvement and indeterminate signs and symptoms. Treatment generally involves systemic therapy and autologous stem-cell transplantation.

Hetero-assembly of a dual ß-amyloid variant peptide system.

Self-assembly of amyloid polypeptides (1) imparts biological effects depending on the size in over 20 amyloid diseases and (2) produces useful yet relatively untapped biomaterials. Unfortunately, our understanding of amyloid polypeptides, as related to biomedical implications and biomaterial applications, is limited by their self-assembling nature. In this study, we report the creation of a dual peptide system, where a pair of ß-amyloid (Aß) variants are not self-assembled but hetero-assembled in the presence of their assembly partners. We provide evidence that the resulting hetero-assemblies share molecular, structural and morphological similarities with typical amyloid self-assemblies formed by a single polypeptide (e.g., Aß). We anticipate that our dual peptide system may readily be adapted for precise control of amyloid assembly, for the study of size-dependent neurotoxicity and precise fabrication of amyloid biomaterials.

Long-term outcomes after biliopancreatic diversion with and without duodenal switch: 2-, 5-, and 10-year data.

BACKGROUND: There are minimal long-term data on biliopancreatic diversion (BPD) with or without duodenal switch (BPD/DS). OBJECTIVES: To investigate the long-term weight loss, co-morbidity remission, complications, and quality of life after BPD and BPD/DS. SETTING: An academic, university hospital in the United States. METHODS: We conducted a retrospective review of patients who underwent BPD or BPD/DS between 1999 and 2011. Outcomes included weight loss measures at 2, 5, and 10-15 years postoperatively; co-morbidity remission; long-term complications; nutritional deficiencies; and patient satisfaction. RESULTS: One hundred patients underwent BPD (34%) or BPD/DS (64%). Mean preoperative body mass index (BMI) was 50.2 kg/m2. Mean follow up was 8.2 years (range: 1-15 yr) with 72% of eligible patients in active follow up at 10-15 years postoperatively. Excess weight loss (EWL) was 65.1% at 2 years, 63.8% at 5 years, and 67.9% at 10-15 years. Approximately 10% higher %EWL was achieved for those with preoperative BMI<50 kg/m2 versus≥50 kg/m2 and patients who underwent BPD/DS versus BPD. Although co-morbidities improved, 37% of patients developed long-term complications requiring surgery. There were no 30-day mortalities; however, there was one mortality from severe malnutrition. Nutritional deficiencies in fat-soluble vitamins, anemia, and secondary hyperparathyroidism were common. Overall, 94% of patients reported satisfaction with their choice of surgery. CONCLUSION: This clinical experience supports the long-term positive safety profile and efficacy of BPD and BPD/DS at a single U.S. center. Higher levels of excess weight loss are achieved by patients with a lower preoperative BMI and BPD/DS. Although nutritional deficiencies and postoperative complications are common, patient satisfaction remains high.

Surgical management and outcomes of patients with marginal ulcer after Roux-en-Y gastric bypass.

BACKGROUND: Marginal ulcers (MUs) are potentially complex complications after Roux-en-Y gastric bypass. Although most resolve with medical management, some require surgical intervention. Many surgical options exist, but there is no standardized approach, and few reports of outcomes have been documented in the literature. The objective of this study was to determine the outcomes of surgical management of marginal ulcers. METHODS: Data from all patients who underwent surgical intervention between 2004 and 2012 for treatment of MU after previous Roux-en-Y gastric bypass were reviewed. RESULTS: Twelve patients with MUs underwent reoperation. Nine patients had associated gastrogastric fistulae (75%). The median time to reoperation was 43 months. Ten patients underwent subtotal gastrectomy, of which 9 had a revision of the gastrojejunal anastomosis and 1 did not. One underwent total gastrectomy with esophagojejunal anastomosis for ulcer after previous revisional partial gastrectomy, and 1 patient underwent video-assisted thoracoscopic truncal vagotomy for persistent ulcer-related bleeding in the early postoperative period. Three patients (25%) experienced postoperative complications associated with revisional surgery requiring reoperation. At median follow-up time of 35 months, 7 patients (58%) had chronic abdominal pain, and 4 patients (33%) had intermittent diarrhea. Three patients (25%) were lost to recent follow-up. None had recurrence of MU. CONCLUSION: Patients can undergo one of several available surgical interventions, including laparoscopic subtotal gastrectomy with gastrojejunostomy revision. Though this appears to offer definitive treatment of MU, its benefits must be weighed against the increased risk of significant postoperative complications and chronic symptoms related to revisional surgery.

Operative risks and survival in veterans with severe aortic stenosis: surgery versus medical therapy.

BACKGROUND: Transcatheter aortic valves were developed as an alternative to surgery for the one third to two thirds of patients with severe aortic stenosis who do not undergo aortic valve replacement. In this study, we examined reasons for medical management of aortic stenosis in relation to operative risks and outcomes for veterans with and without valve replacement. METHODS: The echocardiography database was screened from 2000 to 2007 for severe aortic stenosis. The Society of Thoracic Surgeons risk scores and survival were determined for patients with and without aortic valve replacement. RESULTS: Of 132 severe aortic stenosis patients included, 42% were medically managed. Predicted operative mortality risk was lower for surgical patients than for medical patients (4.5%±4.2% versus 6.8%±5.1%, p=0.002). Overall, the most common reason for medical management of aortic stenosis was assumption that the patient was high risk for surgery (30.4%). The surgery group had significantly higher median survival (92.2 versus 32.4 months) and 5-year survival (71% versus 37%, p<0.001) than the medical group. Cardiac surgery was not consulted in 61% of medically managed patients, of whom only 18% had Society of Thoracic Surgeons risk score of 10 or greater. Aortic valve replacement was an independent predictor of lower mortality (hazard ratio 0.43, p=0.008). CONCLUSIONS: Although operative risk was higher among patients who did not undergo surgery, most were not the 10% or greater required for transcatheter valves. Given the significantly lower survival with medical therapy, aortic valve replacement should be carefully considered for most severe aortic stenosis patients whereas transcatheter aortic valves should be reserved for patients with high operative risks.