Citations

Background: Within the spectrum of gastroesophageal reflux disease (GERD), pathologic reflux applies to the subset of patients with either erosive esophagitis or abnormal esophageal acid exposure on pH-metry, consequences of a dysfunctional antireflux barrier (ARB). Methods: The American Foregut Society (AFS) tasked a 13-member working group of expert foregut surgeons and esophagologists (The ARB Cooperative) to develop a white paper on ARB function, dysfunction, and mechanisms of action of antireflux surgery through discussion of relevant literature summarized herein. Results: The ARB Cooperative concluded that pathologic reflux is a consequence of the interplay between progressive anatomical distortion of the ARB and physiology. Factors contributing to ARB dysfunction include (1) separation of crural diaphragm from the lower esophageal sphincter with widening of the hiatus and diminished crural diaphragm sphincteric function; (2) loss of the intra-abdominal lower esophageal sphincter segment with complete disabling of the flap valve component of the ARB; (3) axial hiatal hernia leading to reflux during swallow-induced lower esophageal sphincter (LES) relaxation, LES hypotension, inspiration related reflux, a lowered threshold for eliciting transient LES relaxations, and increased compliance of the gastroesophageal junction leading to greater diameter of sphincter opening during transient LES relaxations. With regard to antireflux surgery, the objectives include: (1) reduction of hiatal hernia and restoration of the intra-abdominal esophageal segment; (2) repair of the dilated hiatus; (3) restoring flap valve function by modifying gastroesophageal anatomy; and (4) restricting gastroesophageal junction opening during periods of relaxation. Conclusions: This ARB Cooperative white paper supports the concept of there being 3 major inter-related mechanisms promoting ARB competence: the LES as an intrinsic sphincter, the crural diaphragm as an extrinsic sphincter, and the gastroesophageal valve, a mechanical 1-way valve. Pathological reflux occurs with progressive anatomical disruption of the ARB which in turn leads to physiological dysfunction, the severity of which parallels the extent of anatomical disruption. The corollary of this is that the primary mechanism of antireflux surgery is to restore the ARB by eliminating or compensating for its anatomical disruption. It is the hope of the cooperative that understanding the proposed framework will help clinicians and researchers in improving antireflux procedures.

OBJECTIVE Following resection of posterior superior frontal gyrus (PSFG) tumors, patients can experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, the authors sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology. METHODS This was a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon. RESULTS A total of 106 consecutive patients undergoing 123 procedures (21 biopsies, 102 resections) fulfilled inclusion and exclusion criteria. Anaplastic astrocytomas were the most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 27%) (p < 0.0001). The biopsy cohort was more likely to have tumor involvement outside the PSFG (90% vs 62%) (p = 0.011), most commonly in the motor cortex (67% vs 31%) (p = 0.005). Seizures were the most common presenting symptom in the resection cohort (p = 0.017), while motor deficits were more common in the biopsy cohort (58% vs 29%) (p < 0.001). Immediate postoperative neurological deficits occurred in 71 cases (58%), but only 3 of the deficits were permanent at 6 months of follow-up (2%). Postoperative SMA syndrome occurred in 48 cases (47%) and was significantly associated with involvement of the motor cortex (p = 0.018) or cingulate gyrus (p = 0.023), which were also significant in multivariate analysis as risk factors for SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p = 0.51). There were no perioperative deaths, but corpus callosum involvement (p < 0.001), contrast enhancement (p = 0.003), and glioblastoma pathology (p = 0.038) predicted worse overall survival in patients undergoing resection. CONCLUSIONS Nearly half of all patients undergoing resection of PSFG-region tumors experience a postoperative SMA syndrome. Individuals with corpus callosum and/or motor cortex involvement may be at an increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement—in addition to pathology—might serve as predictors of overall survival within this patient population.

Abstract Background Sphingolipids play a crucial role in cellular functions and are essential components of cell membranes, signaling molecules, and lipid metabolism. In particular, ceramide is a key intermediate in sphingolipid metabolism and defects in ceramide metabolism can lead to various inborn errors of metabolism, making ceramides important targets for clinical screening and diagnosis. Detecting altered concentration patterns of sphingolipids is desirable for distinguishing related inborn errors of metabolism for diagnosis and treatment monitoring. Methods We developed a liquid chromatography-tandem mass spectrometry method with a pathway-oriented approach to focus on sphingolipids involved in ceramide metabolism. A total of 47 sphingolipids bearing different head groups and side chains were targeted. Precision/reproducibility, linearity, and spike recovery extraction efficiency tests were performed on plasma and serum samples from confirmed cases of sphingolipidosis. Results Linearity of the method showed the coefficient of determination (r2) for all standards to be &gt;0.99 with a slope of 1.00 ± 0.01. Intra- and interday reproducibility of standards spiked into plasma and serum revealed a coefficient of variation &lt;20%. Spike and recovery assessment showed recovery values of 80%–120% for all standards. Altered levels of sphingolipids from patients with hereditary sensory and autonomic neuropathy caused by pathogenic variants in SPTLC2 and hypomyelinating leukodystrophy related to variants in DEGS1 were detected, in agreement with trends reported in earlier studies confirming the utility of this pathway-centric method. Conclusions This method can serve as a useful tool to simultaneously monitor sphingolipids, enabling screening and diagnosis of inborn errors of ceramide metabolism.

Background: Assessment of orthopaedic surgery trainees is traditionally based on subjective evaluation by faculty. The recent push for value-based health care has placed a premium on improving patient outcomes. As a result, surgical training evaluations for orthopaedic trainees are evolving to include more objective measures to evaluate competency. Purpose: To develop and subsequently demonstrate the efficacy of a novel surgical skills assessment for orthopaedic sports medicine fellows. Study Design: Case series; Level of evidence, 4. Methods: A team of 14 fellowship-trained orthopaedic sports medicine surgeons developed objective scoring rubrics for anterior cruciate ligament reconstruction (ACLR) and rotator cuff repair (RCR) using a modified Delphi process. Rubrics were designed based on 10 surgical steps with a grading scale (1-5) based on core competencies with a maximum summative score of 50. Fourteen orthopaedic fellows across a regionally diverse group of sports medicine–accredited fellowship programs were invited to complete both an ACLR and RCR in a surgical skills laboratory at the beginning and end of their fellowship year. Individual surgical steps, overall performance, and total procedure time were evaluated by a single sports medicine surgeon for both sessions. Results: Thirteen of 14 fellows completed both pre- and post-fellowship assessments. For the ACLR procedure, the pre-fellowship mean summative score was 25.4 (SD, 4.4) and the post-fellowship mean summative score was 38.6 (SD, 4.1), which was a statistically significant improvement ( P < .001). For the RCR procedure, the pre-fellowship mean summative score was 26.6 (SD, 5.4) and the post-fellowship mean summative score was 38.8 (SD, 4.3), which was also a statistically significant improvement ( P < .001). The mean time to completion for the ACLR procedure was 82.3 minutes (SD, 4.3 minutes) pre-fellowship, which improved to 69.7 minutes (SD, 11.6 minutes) post-fellowship ( P = .002). The mean time to completion for the RCR procedure was 85.5 minutes (SD, 5.0 minutes) pre-fellowship, which improved to 76.4 minutes (SD, 7.0 minutes) post-fellowship ( P < .001). Conclusion: This surgical skills program represents the first standardized and reproducible instrument for the evaluation of 2 arthroscopic sports medicine procedures in the United States. Orthopaedic sports medicine fellows improved significantly in aggregate over their fellowship year with regard to the ACLR and RCR. The described program has the potential to serve as both a training tool and formal orthopaedic sports medicine fellow assessment.

Background. Static cold storage is a mainstay of the heart transplantation (HTx) process. However, the temperature distribution within the organ at each stage of HTx is unknown. In this study, we aimed to quantify how long it took for the heart to warm up and cool down and the nature of temperature distribution with the organ at each stage of HTx. Methods. We used high-fidelity computational time-varying biothermal modeling on an anatomical human heart model to model the HTx process in 5 interdependent stages, including cardioplegia, back-table preparation, static cold storage ice box storage and transport, back-table preparation at the recipient institution and warm-up within the recipient body before cross-clamp release. Results. Results indicate that the heart experiences roller-coaster-like temperature changes in stage, including rapid cool down from body temperature to <10 °C within 15 min in stage 1 with a maximum cooling rate of 5 °C/min. This was followed by cooling and extended duration of temperatures <2 °C in the ice box and rapid warming up to body temperature within 10 min at rates of 2 °C/min and 4 °C/min for the left and right sides, respectively, during implantation. Temperature distribution throughout the heart was heterogeneous, with right-sided temperature change occurring nearly 2× faster than on the left side. Conclusions. We present, for the first time, detailed temperature distributions and evolution at each stage of HTx. Quantification of the rapid and heterogeneous temperature changes is crucial to optimize HTx and improve organ viability.

ABSTRACT His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. The ESCRT components Vps4 and Hrs have previously been implicated in cholesterol homeostasis; thus, these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

Summary: Exosomes, or extracellular vesicles, represent the latest cell-free addition to the regenerative medicine toolkit. In vitro preclinical studies have demonstrated the safety and efficacy of exosomes, which vary based on source and biomanufacturing, for a myriad of potential therapeutic applications relevant to skin and soft tissue reconstruction. Primary search was performed in September 2021 on the MEDLINE database via PubMed and Ovid, with focus on articles about therapeutic application of exosomes or extracellular vesicles. In total, 130 articles met criteria for applicability, including early-stage clinical trials, preclinical research studies with in vivo application, and articles applicable to plastic and reconstructive surgery and dermatology. Most studies used animal models of human disease processes, using either animal donor cells to isolate exosomes, or human donor cells in animal models. Exosome technology has catapulted as an acellular therapeutic vehicle with off-the-shelf accessibility. These features eliminate prior threshold for broad adoption of regenerative cell-based therapies into surgical and medical practice. To date, there are no exosome products approved by the US Food and Drug Administration. This review highlights exosomes as the new frontier in regenerative medicine and outlines its preclinical therapeutic applications for cutaneous repair and restoration.