Showing papers by "David Spiegel published in 2020"

Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Abstract: Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.

International Prevalence and Correlates of Psychological Stress during the Global COVID-19 Pandemic.

Abstract: This study reports perceived stress and associated sociodemographic factors from an international sample of adults, during the COVID-19 pandemic. The Perceived Stress Scale (PSS-10) along with socio-demographic questions were conducted between 8 April 2020 and 11 May 2020. The survey was translated from English into five languages. Recruitment was conducted worldwide using social media. A total of 1685 survey responses were collected across 57 countries with eleven countries (≥30 responses/country) included in the sub-analyses. Overall, the mean PSS-10 score was 19.08 (SD = 7.17), reflecting moderate stress compared to previously reported norms. Female gender was associated with a higher PSS score (3.03, p < 0.05) as well as four-year degree holders (3.29, p < 0.05), while adults over 75 years (-7.46, p < 0.05) had lower PSS scores. Personal care composite score (including hours of sleep, exercise, and meditation) was associated with lower PSS scores (-0.39, p < 0.01). Increases in personal care and changes in work expectations were associated with lower PSS scores (-1.30 (p < 0.05) and -0.38 (p < 0.01), respectively). Lower total PSS scores were reported in Germany (-4.82, p < 0.01) compared to the global response sample mean. This information, collected during the initial period of global mitigation orders, provides insight into potential mental health risks and protective factors during crises.

Post-Traumatic Growth, Dissociation, and Sexual Revictimization in Female Childhood Sexual Abuse Survivors:

Abstract: Background:Childhood sexual abuse (CSA) survivors are at high risk of sexual revictimization. At the same time, some survivors report positive transformations resulting from the traumatic experienc...

Glycation and Serum Albumin Infiltration Contribute to the Structural Degeneration of Bioprosthetic Heart Valves

Abstract: Background Bioprosthetic heart valves (BHV) are widely used to treat heart valve disease but are fundamentally limited by structural valve degeneration (SVD). Non-calcific mechanisms of SVD entirely account for approximately 30% of SVD cases and contribute to calcific SVD but remain understudied. Glycation mechanisms have not been previously associated with SVD, despite being established as degenerative in collagenous native tissues. Objectives To determine whether blood component infiltration-based glycation and concomitant human serum albumin (HSA) deposition contribute mechanistically to SVD. Methods Immunohistochemistry (IHC) was used to identify advanced glycation end-products (AGEs) and serum albumin accumulation in 45 aortic valve BHV explanted due to SVD, glutaraldehyde-treated bovine pericardium (BP) incubated in vitro in glyoxal and HSA, and rat subcutaneous BP implants. Structural impacts of glycation-related mechanisms were evaluated by second harmonic generation (SHG) collagen imaging. Hydrodynamic effects of valve glycation and concomitant HSA exposure were studied with an ISO-5840-compliant pulse duplicator system using surgical grade BHV. Results All 45 clinical explants and in vitro-incubated BP demonstrated accumulated AGE and HSA compared to un-implanted, un-exposed BHV. SHG revealed instigation of collagen malalignment similar to that in SVD explants by glycation and HSA infiltration. Rat subdermal explants also showed AGE and serum albumin accumulation. Pulse duplication demonstrated significantly reduced orifice area and increased pressure gradient and peak fluid velocity following glyoxal and HSA incubations. Conclusions Glycation and concomitant HSA infiltration occur in clinical BHV and contribute to structural and functional degeneration of leaflet tissue, thus representing novel, interacting mechanisms of BHV SVD.

Inviting Scientific Discourse on Traumatic Dissociation: Progress Made and Obstacles to Further Resolution

Abstract: This paper emerged from a five-part exchange on trauma-related dissociation in forensic contexts between the authors and Merckelbach and colleagues (2017–2019). We find important areas of consensus, including that trauma exposure is associated with depersonalization and, occasionally, memory errors; reports of dissociative symptoms may be elevated due to non-trauma factors; error rates for diagnosing dissociative identity disorder are low; and multiple sources of information are required for assessing any symptom, including dissociation, in forensic contexts. Our goals in this paper are to accurately summarize our evidence-based position about dissociation as it relates to forensic contexts and to call for more scientific discourse and less motivated skepticism by all involved scholars. We enumerate and demonstrate our critics’ reliance on eight forms of rhetoric that are largely rejected by the scientific community. We illustrate these forms of argument using Merckelbach et al.’s published responses in this lengthy debate as exemplars. Recognition of our critics’ reliance on these forms of argumentation is crucial to making further substantial progress in this debate. We argue that recovered memories of trauma should be evaluated in court using the same criteria that would be used with any other memory, including seeking out and evaluating corroborating and disconfirming evidence. We conclude by emphasizing the importance of comprehensive, unbiased assessments of dissociation in reported trauma-related forensic cases and suggest areas where research is needed.

Identification With the Aggressor and Inward and Outward Aggression in Abuse Survivors.

Abstract: Childhood abuse survivors may display both inward and outward aggression manifested in self-injurious behavior (SIB) and violent acts toward others. Scrutinizing the literature reveals that the relational dynamics between victims and their perpetrators might be involved in these phenomena. Yet, research on this subject matter has been sparse. Filling this gap, this study investigated the contribution of the singular bonds between victims and their perpetrators, known as identification with the aggressor, in explaining survivors' aggression. The study was conducted among 306 Israeli college/university students who reported a history of childhood abuse. Results revealed that levels of adopting the perpetrator's experience, identifying with the perpetrator's aggression, and replacing one's agency with that of the perpetrator were significantly associated with survivors' inward and outward aggression. Moreover, profile type-that is, having high versus low levels of identification with the aggressor-was implicated in participants' SIBs, urge to harm others, and violent acts toward others, above and beyond the effects of gender and posttraumatic stress disorder (PTSD) symptoms. The present findings suggest that identification with the aggressor might make survivors prone to the re-enactment of past abusive dynamics, which, in turn, could eventuate in aggression toward themselves and others.

Wrangling with p-values versus effect sizes to improve medical decision-making: A tutorial.

Abstract: The most pervasive and damaging myth in clinical research is that the smaller the p-value, the stronger the hypothesis. In reality, the p-value primarily reflects the quality of research design decisions. The most common proposal to avoid misleading conclusions from clinical research requires the appropriate use of effect sizes, but which effect size, used when and how, is an open question. A solution is proposed for perhaps the most common problem in clinical research, the comparison between two populations, for example, comparison of two treatments in a randomized clinical trial or comparison of high risk versus low risk individuals in an epidemiological study: the success rate difference or equivalently the number needed to treat/take (NNT).

Association between Anterior Cingulate Neurochemical Concentration and Individual Differences in Hypnotizability.

Abstract: Hypnosis is the oldest form of Western psychotherapy and a powerful evidence-based treatment for numerous disorders. Hypnotizability is variable between individuals; however, it is a stable trait throughout adulthood, suggesting that neurophysiological factors may underlie hypnotic responsiveness. One brain region of particular interest in functional neuroimaging studies of hypnotizability is the anterior cingulate cortex (ACC). Here, we examined the relationships between the neurochemicals, GABA, and glutamate, in the ACC and hypnotizability in healthy individuals. Participants underwent a magnetic resonance imaging (MRI) session, whereby T1-weighted anatomical and MEGA-PRESS spectroscopy scans were acquired. Voxel placement over the ACC was guided by a quantitative meta-analysis of functional neuroimaging studies of hypnosis. Hypnotizability was assessed using the Hypnotic Induction Profile (HIP), and self-report questionnaires to assess absorption (TAS), dissociation (DES), and negative affect were completed. ACC GABA concentration was positively associated with HIP scores such that the higher the GABA concentration, the more hypnotizable an individual. An exploratory analysis of questionnaire subscales revealed a negative relationship between glutamate and the absorption and imaginative involvement subscale of the DES. These results provide a putative neurobiological basis for individual differences in hypnotizability and can inform our understanding of treatment response to this growing psychotherapeutic tool.

Morning chronotype is a protective factor against chemotherapy-induced hot flashes in premenopausal women with breast cancer.

Abstract: Adjuvant chemotherapy in patients with breast cancer often causes hot flashes, impairing quality of life. However, the chronobiological or psychiatric factors associated with the development of chemotherapy-induced hot flashes (CIHFs) remain undetermined. The purpose of this study was to investigate whether chronotype was associated with the incidence of CIHFs. A total of 119 premenopausal women with non-metastatic breast cancer awaiting adjuvant chemotherapy after surgery without hot flashes were included. The presence of CIHF was defined as having moderate to severe hot flashes, as measured by the subscale of hot flashes in the Menopause Rating Scale, at 4 weeks after the completion of chemotherapy. Chronotype (Morning/Intermediate/Evening) was assessed with the Composite Scale of Morningness before adjuvant chemotherapy. To examine the association between chronotype and CIHF, we built logistic regression models, adjusting for age, body mass index, sleep quality, and radiation therapy. CIHF occurred in 50.4% of participants. Morning type was inversely associated with CIHF (reference: Intermediate type, odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16–0.94; p = 0.040) in the univariate model, and the association remained significant (OR, 0.37; CI, 0.13–0.96; p = 0.045) after adjusting for age, body mass index, sleep quality, and radiation therapy. Morning chronotype is a protective factor against the development of CIHF in patients with breast cancer. Chronotypes should be assessed and considered in the prediction and management of CIHF.

Brain and Physiological Markers of Autonomic Function Are Associated With Treatment-Related Improvements in Self-Reported Autonomic Dysfunction in Veterans With Gulf War Illness: An Exploratory Pilot Study.

Abstract: BackgroundGulf War Illness (GWI) is a poorly understood condition characterized by a constellation of mood, cognitive, and physical symptoms. A growing body of evidence demonstrates autonomic nervo...

Multi-site Validation of a SARS-CoV-2 IgG/IgM Rapid Antibody Detection Kit

Abstract: Deaths from coronavirus disease (COVID-19) have exceeded 300,000 persons globally, calling for rapid development of mobile diagnostics that can assay widespread prevalence and infection rates. Data provided in this study supports the utility of a newly-designed lateral flow immunoassay (LFA) for detecting SARS-CoV-2 IgM and IgG antibodies. We employed a clinical cohort of 1,892 SARS-CoV-2 patients and controls, including individuals diagnosed by RT-qPCR at Yale New Haven Hospital, The First Affiliated Hospital of Anhui Medical University, the Chinese Center for Disease Control and Prevention of Hefei City (Hefei CDC), Anhui Province (Anhui Province CDC), and Fuyang City (Fuyang CDC). The LFA studied here detects SARS-CoV-2 IgM and IgG antibodies with a specificity of 97.9-100% for IgM, 99.7-100% for IgG, and sensitivities ranging from 94.1-100% for patients >14-days post symptom onset. Sensitivity decreases in patients

Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue.

Abstract: Although there is ample evidence that the advanced glycation end-product (AGE) glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane. We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch's membrane, and choroid: all regions of the eye impacted by age-related macular degeneration. Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.

Fluorescent stem peptide mimics: In situ probes for peptidoglycan crosslinking.

Abstract: Understanding the mechanisms of bacterial cell wall synthesis is essential for microbiology and medicine alike. A key step in this process is peptidoglycan crosslinking, which confers mechanical strength to the cell wall and represents a target for numerous classes of antibiotics. However, the biology of crosslinking remains poorly understood due to a lack of tools for studying the reaction in vivo. Recently, we developed a class of synthetic probes called fluorescent stem peptide mimics (FSPMs) that meet this need, allowing quantification and localization of crosslinking activity in live bacteria. We have utilized FSPMs to describe novel aspects of peptidoglycan synthesis in the human pathogen, Staphylococcus aureus. To enable wider use of our methodology, we provide detailed protocols herein for the synthesis of FSPMs, labeling of live bacteria, and evaluation of crosslinking by flow cytometry and super-resolution microscopy. We believe that FSPMs, together with complementary biosynthetic probes and traditional bacteriologic methods, will help to advance our understanding of peptidoglycan biology and accelerate the search for new antibiotics.

The Frequency of Mediastinal Injury in Acute Posterior Sternoclavicular Dislocations: A Multicenter Study

Abstract: Background Acute posterior sternoclavicular dislocations (APSCD) are rare injuries that historically have prompted concern for injury to the great vessels and other mediastinal structures from initial trauma or subsequent treatment, resulting in the recommendation that a thoracic or vascular surgeon be present or available during operative treatment. The objectives of the study were to characterize the demographic, clinical, and radiographic characteristics of a large series of APSCDs in skeletally immature patients and to describe the rate and nature of any vascular or mediastinal complications that occurred during treatment. Methods Following Institutional Review Board approval, records of consecutive patients under 25 years of age treated for APSCD were collected from each of 6 participating centers. Only acute injuries (sustained fewer than 10 days before presentation) were included. Patient demographics, injury mechanism, associated mediastinal injuries, and need for thoracic/vascular surgery were recorded. Mediastinal structures injured or compressed by mass effect were specifically characterized by review of preoperative computed tomography imaging. Results Review identified 125 patients with a mean age of 14.7 years; 88% were male. APSCD most commonly resulted from a sporting injury (74%) followed by falls from standing height (10%) and high-energy motor vehicle trauma (10%). The most common finding on cross-sectional imaging was compression without laceration of the ipsilateral brachiocephalic vein (50%). Eleven patients had successful closed reduction, and 114 (90%) had open reduction and internal fixation, with 25 failed or unstable closed reductions preceding open treatment. There were no vascular or mediastinal injuries during reduction or fixation that required intervention. Conclusions In this multicenter series of 125 APSCDs no injuries to the great vessels/mediastinal structures requiring intervention were identified. Although more than half of patients had evidence of extrinsic vascular compression at the time of injury, careful open reduction of acute injuries can be safely performed. Although vascular injuries following APSCD seem to be quite rare, vascular complications can be catastrophic. Treating providers should consider these data and their own institutional resources to maximize patient safety during the treatment of APSCD. Level of evidence Level III-therapeutic case control study.

Deterioration of Glutaraldehyde Crosslinked Heterograft Biomaterials due to Advanced Glycation End Product Formation and Serum Albumin Infiltration

Abstract: Bioprosthetic heart valves (BHV) are fabricated from glutaraldehyde cross-linked heterograft tissue, such as bovine pericardium (BP) or porcine aortic valves. BHV develop structural valve degeneration (SVD), often with calcification, requiring BHV replacement. Advanced glycation end products (AGE) are post-translational, nonenzymatic carbohydrate protein modifications. AGE are present in SVD-BHV clinical explants and not detectable in unimplanted BHV. Here, we studied the hypothesis that BHV susceptibility to AGE formation and serum protein infiltration results in deterioration of both leaflet collagen structure and mechanical properties. In vitro experiments studied BP and porcine collagen sponges (CS) for susceptibility to AGE formation using 14C-glucose and 14C-glyoxal with and without bovine serum albumin (BSA), as a model serum protein. The results showed AGE formation is a rapid and progressive process. BSA co-incubations reduced glyoxal and glucose uptake by BP and CS. Incubating BP in BSA caused a substantial increase in BP mass, enhanced by glyoxal co-incubation. Per two-photon microscopy, BP with AGE formation and BSA infiltration each induced significant disruption in collagen microarchitecture, with loss of collagen alignment and crimp. These effects are cumulative with the greatest disruption occurring when there was both AGE formation and BSA infiltration. Uniaxial testing of CS demonstrated that AGE formation, together with BSA uptake compared to controls, caused a significant deterioration in mechanical properties with a loss of viscoelastic relaxation and increased stiffness. It is concluded that AGE-BSA associated collagen structural disruption and deterioration of mechanical properties contribute to SVD.

Bifunctional Small Molecules That Mediate the Degradation of Extracellular Proteins

Abstract: Targeted protein degradation (TPD) has emerged as a promising and exciting therapeutic strategy. The majority of existing TPD technologies rely on the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modularly designed, bifunctional synthetic molecules called MoDE-As (Molecular Degraders of Extracellular proteins through the Asialoglycoprotein receptor (ASGPR)), which are capable of mediating the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and the ASGPR, which is expressed primarily on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing bifunctional molecules that induce the degradation of both antibody and pro-inflammatory cytokine proteins. To our knowledge, these data represent the first experimental evidence that non-proteinogenic, synthetic molecules can be employed for the TPD of extracellular proteins both in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

Open Reduction and Suture Fixation of Acute Sternoclavicular Fracture-Dislocations in Children.

Abstract: Background Acute sternoclavicular fracture-dislocation is associated with high-energy trauma and is being increasingly recognized in children1. These injuries are associated with compression of mediastinal structures and can be life-threatening1. The management of acute sternoclavicular fracture-dislocation includes closed reduction or open surgical stabilization; however, limited success is reported with closed reduction2,3. To our knowledge, there are no detailed descriptions of open reduction and suture fixation of acute sternoclavicular fracture-dislocation in children. Description Following diagnosis of acute sternoclavicular fracture-dislocation, the timing of surgical treatment is determined according to several patient and surgical factors. Among patients with hemodynamic instability, respiratory compromise, or evidence of asymmetric perfusion, surgical treatment is needed on an emergency basis. In the absence of these factors, surgical treatment can be performed on an urgent basis. It is important to communicate with vascular or thoracic surgeons prior to proceeding to the operating room because of the rare case in which advanced surgical access or vascular repair is required. In the operating room, general anesthesia and large-bore intravenous access are required. Patients are positioned supine on a radiolucent table, and a small bump is placed between the scapulae to elevate the medial aspect of the clavicle. The contralateral sternoclavicular joint and medial aspect of the clavicle should be prepared into the sterile field, as well as both sides of the groin in case vascular access is needed. A 6 to 8-cm incision is centered on the medial aspect of the clavicle, extending to the manubrium. Standard dissection to the clavicle is performed, and care is taken to maintain the integrity of the sternoclavicular ligament complex. Circumferential dissection of the medial clavicular metaphysis is usually required in order to mobilize the dislocated fragment. Reduction of the physeal fracture usually requires axial traction and extension of the ipsilateral shoulder with the aid of a reduction clamp on the medial clavicular metaphysis. In some cases, a Freer elevator can be placed between the metaphysis and epiphysis to shoehorn the clavicle from posterior to anterior. Once reduced, the fracture-dislocation is usually stable; however, the reduction is augmented with suture fixation. The sternoclavicular joint capsule should be repaired if disrupted, and the incision should be closed in layers. Postoperatively, the arm is placed in a sling, and range of motion is commenced at 4 weeks. Alternatives Alternative management of acute sternoclavicular fracture-dislocation includes closed reduction, plate fixation4, and ligament reconstruction5. Rationale In our experience, closed reduction is often unsuccessful, which is consistent with the experiences reported by other authors2,3. In addition, suture fixation is sufficient and plate fixation is not required because this injury is relatively stable following reduction. Lastly, ligament reconstruction with use of autograft or allograft may be indicated but is more relevant in chronic cases with injury or attenuation of the sternoclavicular ligament complex. Open reduction allows for direct visualization of the fracture reduction, and suture fixation allows for increased stability without the need for hardware or secondary surgical procedures. Expected Outcomes We expect patients to achieve full range of motion and strength without any joint instability as reported by Waters et al.3. Important Tips There is an inherent risk of vascular injury with open reduction and suture fixation. This risk is mitigated with perioperative planning and consultation with vascular or thoracic surgeons. General surgeons should always be available when these procedures are performed in case of vascular issues or emergencies.It is sometimes difficult to reduce the dislocation, but additional maneuvers allow for controlled reduction of the displaced clavicle, such as using a Freer elevator and serrated clamp.Assessing fracture reduction can be difficult intraoperatively. Including the contralateral sternoclavicular joint in the sterile surgical field can be helpful in assessing fracture reduction and osseous contour.

Universal abt compounds and uses thereof

Abstract: Among other things, the present disclosure provides compounds comprising universal antibody binding moieties and targeting moieties. In some embodiments, provided compounds recruit various types of antibodies to diseased cells such as cancer cells, and induce immune activities to kill such cells. Provided technologies are useful for treating various diseases including cancer.

Adding value in single-event multilevel surgery (SEMLS) for cerebral palsy patients with crouch gait: A retrospective study showing value added by a second surgeon

Abstract: Background: Single event multilevel surgery (SEMLS) is a common treatment for ambulatory children with cerebral palsy (CP) who have bony and soft-tissue abnormalities at multiple levels within the lower extremities. We introduced a second surgical team to enable simultaneous bilateral procedures and assessed the cost savings resulting from simultaneous bilateral SEMLS versus staged bilateral SEMLS. Methods: We retrospectively reviewed patients with spastic diplegia treated by simultaneous or staged bilateral SEMLS from January 1, 2010, to December 1, 2015. We evaluated procedures performed, surgical duration, estimated blood loss (EBL) and blood transfusions, length of inpatient and rehabilitation admission, complications, and associated costs (normalized to 2015 dollars). Results: Eighteen eligible patients were identified with no significant differences in age, gender, or total number of procedures. Introduction of simultaneous bilateral SEMLS reduced costs by an average of $161,267. In this group, total length of stay was less for inpatient and rehabilitation stay. EBL was similar between the two groups: 683 mL versus 532 mL (P value 0.24). Thirty-six percent of the patients in the simultaneous group required a transfusion versus 0% in the staged group. Complications (n=3) in the staged group included infection, failure of fixation, and additional procedure for femoral derotation. Complications (n=2) in the simultaneous group included failure of fixation and readmission for symptomatic anemia. Conclusions: While some may favor staging interventions, simultaneous bilateral SEMLS with two surgical teams is a safe and effective alternative to help improve ambulatory function in CP patients associated with significant cost savings. The risk of allogenic blood transfusion may be increased with simultaneous bilateral SEMLS. Level of Evidence: Level IV.

Advanced glycation end-product breaking biocatalysts

Abstract: In various aspects and embodiments the invention provides compositions and methods for removing glucosepane from one or more proteins in a subject. In certain embodiments, the method comprises administering to the subject an effective amount of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13, or a biologically active fragment thereof.