Social isolation is defined, in psychological terms, as the absence of meaningful social interactions, contacts, and relationships with family and friends, with neighbors. It can occur on an individual level and, on a broader level, within “society at large.” In the United States, three main groups of socially isolated individuals can be identified: people who reside in assisted-living facilities, nursing homes, or hospices, people suffering from “persistent loneliness” and people incarcerated in jails or prisons who are housed in involuntary solitary confinement. In this chapter, we discuss the psychological and neurobiological effects of isolation, using both animal models as well as direct studies of humans experiencing these conditions. Only by understanding the impact of isolation on the brain and the mechanisms that underlie these changes can we hope to develop interventions that prevent them from occurring in the first place. This knowledge may also contribute to the efforts of psychologists, clinicians, and community health leaders to employ evidence-based prevention programs to mitigate the risk of isolation-induced physical and psychological damage in humans.
Background: Health Locus of Control (HLOC) is the degree to which individuals believe that their health outcomes are controlled by 'external' factors - environmental forces, chance, fate, other people, or some higher power - or by 'internal' factors - their own behavior or action. Most of the literature on HLOC associates an Internal Health Locus of Control (IHLOC) to pro-health behaviors and better health outcomes. However, a few studies also suggest that in chronic illnesses, an External Health Locus of Control (EHLOC) could be beneficial with respect to pro-health behaviors and perceptions of Quality of Life (QoL), challenging assumptions about what leads to the most effective psychological coping in the face of difficult circumstances. Multiple sclerosis (MS) is a chronic immune condition of the central nervous system and the most frequent cause of non-traumatic disability in young adults, often despite treatment. Method: The primary goal of this non-experimental, cross-sectional, quantitative study of 89 individuals with MS was to explore the HLOC of individuals with MS, and to identify whether holding an EHLOC positively impacts the MS patients' perceived QoL while taking into consideration their level of disability. Results: This research found that individuals with higher disability scores tended to hold more EHLOC beliefs, and that there was a significant correlation between QoL and holding EHLOC beliefs. Conclusion: This study was able to capture the importance of control beliefs in the QoL of individuals with MS with higher disability. The clinical implications of the findingare explored and areas for further research are suggested.
Electrical stimulation is used to elicit muscle contraction and can be utilized for neurorehabilitation following spinal cord injury when paired with voluntary motor training. This technology is now an important therapeutic intervention that results in improvement in motor function in patients with spinal cord injuries. The purpose of this review is to summarize the various forms of electrical stimulation technology that exist and their applications. Furthermore, this paper addresses the potential future of the technology.
Background Studies of pedal cyclist injuries have largely focused on individual injury categories, but every region of the cyclist’s body is exposed to potential trauma. Real-world injury patterns can be complex, and isolated injuries to one body part are uncommon among casualties requiring hospitalization. Latent class analysis (LCA) may identify important patterns in heterogeneous samples of qualitative data. Methods Data were taken from the Trauma Quality Improvement Program of the American College of Surgeons for 2017. Inclusion criteria were age 18 years or less and an external cause of injury code for pedal cyclist. Injuries were characterized by Abbreviated Injury Scale codes. Injury categories and the total number of injuries served as covariates for LCA. A model was selected on the basis of the Akaike and Bayesian information criteria and the interpretability of the classes. Associations were analyzed between class membership and demographic factors, circumstantial factors, metrics of injury severity, and helmet wear. Within-class associations of helmet wear with injury severity were analyzed as well. Results There were 6151 injured pediatric pedal cyclists in the study sample. The mortality rate was 0.5%. The rate of helmet wear was 18%. LCA yielded a model with 6 classes: ‘polytrauma’ (5.5%), ‘brain’ (9.0%), ‘abdomen’ (11.0%), ‘upper limb’ (20.9%), ‘lower limb’ (12.4%), and ‘head’ (41.2%). Class membership had highly significant univariate associations with all covariates except insurance payer. Helmet wear was most common in the ‘abdomen’ class and least common in the ‘polytrauma’ and ‘brain’ classes. Within classes, there was no association of helmet wear with severity of injury. Conclusions LCA identified 6 clear and distinct patterns of injury with varying demographic and circumstantial associations that may be relevant for prevention. The rate of helmet wear was low, but it varied among classes in accordance with mechanistic expectations. LCA may be an underutilized tool in trauma epidemiology.
Background Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE. Methods This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC 0-tlqc ) will be calculated to estimate dose-linear pharmacokinetics. Perspective Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547.
Background Cancer cells have an imbalance in oxidation-reduction (redox) homeostasis. Understanding the precise mechanisms and the impact of the altered redox microenvironment on the immunologic reaction to tumors is limited. Methods We isolated exosomes from ovarian cancer cells through ultracentrifuge and characterized by Western-blots and Nanoparticle Tracking Analysis. 2D, 3D-coculture tumor model, and 3D live cell imaging were used to study the interactions between tumor cells, macrophages and CD3 T cells in vitro. The role of exosomal miR-155-5p in tumor growth was evaluated in xenograft nude mice models and immune-competent mice models. Flow cytometry and flow sorting were used to determine the expression levels of miR-155-5p and PD-L1 in ascites and splenic macrophages, and the percentages of CD3 T cells subpopulations. Results The elevation of reactive oxygen species (ROS) greatly downregulated exosomal miR-155-5p expression in tumor cells. Neutralization of ROS with N-acetyl-L-cysteine (NAC) increased the levels of miR-155-5p in tumor exosomes that were taken up by macrophages, leading to reduction of macrophage migration and tumor spheroid infiltration. We further found that programmed death ligand 1 (PD-L1) is a functional target of miR-155-5p. Co-culture of macrophages pre-treated with NAC-derived tumor exosomes or exosomal miR-155-5p with T-lymphocytes leading to an increased percentage of CD8 ⁺ T-lymphocyte and a decreased CD3 ⁺ T cell apoptosis through PD-L1 downregulation. Tumor growth in nude mice was delayed by treatment with NAC-derived tumor exosomes. Delivery of tumor exo-miR-155-5p in immune-intact mice suppressed ovarian cancer progression and macrophage infiltration, and activated CD8 ⁺ T cell function. It is of note that exo-miR-155-5p inhibited tumor growth more potently than the PD-L1 antibody, suggesting that in addition to PD-L1, other pathways may also be targeted by this approach. Conclusions Our findings demonstrate a novel mechanism, ROS-induced down-regulation of miR-155-5p, by which tumors modulate the microenvironment that favors tumor growth. Understanding of the negative impact of ROS on the tumor immune response will improve current therapeutic strategies. Targeting miR-155-5p can be an alternative approach to prevent formation of an immunosuppressive TME through downregulation of PD-L1 and other immunosuppressive factors. Graphical Abstract
Study design: Survey OBJECTIVES: Better understand the demographics of pain after spinal cord injury (SCI). Setting: Academic Level 1 trauma center and SCI Model System. Methods: A survey including general demographic questions, questions of specific interest to the authors, the standardized SCI Pain Instrument (SCIPI), International SCI Pain Data Set, Basic form (ISCIPDS:B), Patient Reported Outcomes Measurement Information System (PROMIS) neuropathic 5a (PROMIS-Neur), and PROMIS nociceptive 5a (PROMIS-No). Results: 81% of individuals with SCI experience chronic pain and 86% of individuals with pain have neuropathic pain. 55% of individuals had shoulder pain. Females and those who recall >5/10 pain during initial hospital stay had significantly higher PROMIS-Neur scores. Completeness of injury correlates inversely with the degree of neuropathic pain. Those who recall >5 pain during the initial hospital stay and those who reported the worst or second worst pain as being shoulder pain had significantly higher PROMIS-No scores. Lumbosacral injuries trended towards higher PROMIS-No scores and had the highest PROMIS-Neur scores. Those with tetraplegia were more likely to develop shoulder pain and those with shoulder pain had higher PROMIS-No scores. Conclusions: Chronic pain is almost universal in patients with SCI. Pain is more commonly reported as neuropathic in nature and females reported more neuropathic pain than males. Physicians should monitor for nociceptive shoulder pain, particularly in those with tetraplegia. Patients with incomplete injuries or lumbosacral injuries are more likely to report higher levels of neuropathic pain and pain levels should be monitored closely. Those with more neuropathic and nociceptive pain recall worse pain at initial hospitalization. Better understanding pain demographics in this population help screen, prevent and manage chronic pain in these patients.
Background Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC). Methods Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression. Results We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth. Conclusions Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.
Purpose: Osteochondral allograft (OCA) transplantation is a restorative technique for addressing articular cartilage defects by transferring mature viable chondrocytes with subchondral bone into size-matched lesions. The purpose of this study was to compare differences in clinical and functional outcomes in patients treated with OCA for osteochondral defects compared with isolated chondral pathology. Methods: A retrospective review identified patients who underwent OCA transplantation and grouped them into osteochondral or isolated chondral pathology. Demographic data, surgical history, lesion characteristics, complications, and rate of subsequent surgery were reviewed. The review included 86 patients (24 osteochondral, 62 chondral) with a mean follow-up of 5.4 ± 1.4 years. Outcome measures included the Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS, JR.), International Knee Documentation Committee (IKDC), and Short Form Health Survey (SF-12) physical scores. Failure was defined to include revision OCA, graft removal, conversion to ACI, or conversion to arthroplasty. Results: The average age at surgery was 32.3 and 37.3 years for the osteochondral and chondral groups, respectively (P = 0.056). The medial femoral condyle was the most common defect location in both groups. P < 0.05 was considered statistically significant. Patients with osteochondral pathology had significantly greater KOOS JR., IKDC, and SF-12 scores (P < 0.05), and fewer failures were reported in the osteochondral group (8.3% versus 32.3%, P = 0.045). When controlling for age, sex, laterality, BMI, and presence of a concomitant procedure, patients with osteochondral pathology were found to have better KOOS and IKDC scores, but there was no difference in SF12 scores or rates of failure between groups. Conclusion: The findings of this study indicate that patients undergoing OCA for osteochondral defects may have greater functional outcomes and similar failure rates compared with OCA transplantation for isolated chondral pathology.
Background Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. Methods (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. Results (1) Proteins encoded by AKT3 ( AKT3Q60H ) and AKT1 ( AKT1Q61H ) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1 , respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10 –8 ). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. Conclusions Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.
Background Patients with cancer constitute a large and increasing segment of patients who receive unscheduled hospital-based care due to treatment-related symptoms and disease progression. The initial hospital-based touchpoint for these unscheduled hospitalizations is often the emergency department. Traditional models of emergency department and inpatient hospital-based care are saturated and incapable of scaling to accommodate the future, increased needs projected for this population. New models of care are necessary to address this gap. Acute home-based care is a promising tool potentially providing patient-centric, efficient care to eligible patients. Methods We applied Porter’s Five Forces framework that addresses the bargaining power of buyers and suppliers, threat of substitutes and new entrants, and industry rivalries plus the sixth force of regulation to clarify the factors that will promote or challenge the adoption of a home-based cancer care referral model before or following emergency department visits. Exploring this framework provides insights into the complexities of scaling an acute home-based cancer care model and highlights ways for health systems including hospitals, emergency departments, physician groups, and individual emergency physicians and oncologists to optimize their roles in this emerging model of care. Results We found that current workforce shortages, as well as workflow, infrastructure, and regulatory complexities, pose major challenges that unless carefully addressed may restrict the growth of acute home-based cancer care. Additional uncertainties persist around appropriate payment models and the competitive landscape. Key promoting factors include the recognized need in the cancer community and among payers for new models to decrease unscheduled hospitalizations and emergency department visits as well as the uptake of home-based and technology-enabled solutions during the COVID-19 pandemic. A better understanding of these forces helps to clarify the risks and opportunities as new entrants build their programs. Conclusions Acute home-based cancer care is a promising tool to complement traditional outpatient clinics, emergency departments, and inpatient hospital-based models of cancer care. New technologies and policies increasingly enable a broader scope of cancer care in the home setting.
Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15–12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.
Introduction De-escalation of breast cancer treatment aims to reduce patient and financial toxicity without compromising outcomes. Level I evidence and National Comprehensive Cancer Network guidelines support omission of adjuvant radiation in patients aged >70 y with hormone-sensitive, pT1N0M0 invasive breast cancer treated with endocrine therapy. We evaluated radiation use in patients eligible for guideline concordant omission of radiation. Methods Subgroup analysis of patients eligible for radiation omission from two pooled randomized controlled trials, which included stage 0-III breast cancer patients undergoing breast conserving surgery, was performed to evaluate factors associated with radiation use. Results Of 631 patients, 47 (7.4%) met radiation omission criteria and were treated by 14 surgeons at eight institutions. The mean age was 75.3 (standard deviation + 4.4) y. Majority of patients identified as White (n = 46; 97.9%) and non-Hispanic (n = 44; 93.6%). The mean tumor size was 1.0 cm; 37 patients (88.1%) had ductal, 4 patients (9.5%) had lobular, and 17 patients (40.5%) had low-grade disease. Among patients eligible for radiation omission, 34 (72.3%) patients received adjuvant radiation. Those who received radiation were significantly younger than those who did not (74 y, interquartile range = 4 y, versus 78 y, interquartile range = 11 y, P = 0.03). There was no difference in radiation use based on size (P = 0.4), histology (P = 0.5), grade (P = 0.7), race (P = 1), ethnicity (P = 0.6), institution (P = 0.1), gender of the surgeon (P = 0.7), or surgeon (P = 0.1). Conclusions Fewer than 10% of patients undergoing breast conservation met criteria for radiation omission. Nearly three-quarters received radiation therapy with younger age being a driver of radiation use, suggesting ample opportunity for de-escalation, particularly among younger eligible patients.
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