Intravital imaging of three different microvascular beds in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have sequelae that extend well beyond the alveoli into the pulmonary vasculature and, perhaps, beyond to the brain and other organs. Because of the dynamic events within blood vessels, histology does not report platelet and neutrophil behavior. Because of the rapid nontranscriptional response of these cells, neither single-cell RNA sequencing nor proteomics report robustly on their critical behaviors. We used intravital microscopy in level-3 containment to examine the pathogenesis of SARS-CoV-2 within 3 organs in mice expressing human angiotensin converting enzyme 2 (ACE-2) ubiquitously (CAG-AC-70) or on epithelium (K18-promoter). Using a neon-green SARS-CoV-2, we observed both the epithelium and endothelium infected in AC70 mice but only the epithelium in K18 mice. There were increased neutrophils in the microcirculation but not in the alveoli of the lungs of AC70 mice. Platelets formed large aggregates in the pulmonary capillaries. Despite only neurons being infected within the brain, profound neutrophil adhesion forming the nidus of large platelet aggregates were observed in the cerebral microcirculation, with many nonperfused microvessels. Neutrophils breached the brain endothelial layer associated with a significant disruption of the blood-brain-barrier. Despite ubiquitous ACE-2 expression, CAG-AC-70 mice had very small increases in blood cytokine, no increase in thrombin, no infected circulating cells, and no liver involvement suggesting limited systemic effects. In summary, our imaging of SARS-CoV-2-infected mice gave direct evidence that there is a significant perturbation locally in the lung and brain microcirculation induced by local viral infection leading to increased local inflammation and thrombosis in these organs.

Exploratory Evaluation of the Relationship Between iNKT Cells and Systemic Cytokine Profiles of Critically Ill Patients with Neurological Injury.

BACKGROUND: Neurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury. METHODS: We conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (TH1) and T helper 2 (TH2) cytokines, by multiplex bead-based assay. RESULTS: Invariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH2/TH1 cytokines early after injury (days 1 - 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH2/TH1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4- iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified. CONCLUSIONS: Critically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH2/TH1 cytokine ratios. This work provides further support for a brain-immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system.

Designing Well-Being: Using Design Thinking to Engage Residents in Developing Well-Being Interventions.

PROBLEM: Improving well-being in residency requires solutions that focus on organizational factors and the individual needs of residents, yet there are few examples of successful strategies to address this challenge. Design thinking (DT), or human-centered design, is an approach to problem-solving that focuses on understanding emotions and human dynamics and may be ideally suited to tackling well-being as a complex problem. The authors taught residents to use DT techniques to identify, analyze, and address organizational well-being challenges. APPROACH: Internal medicine residents at the University of California, San Francisco completed an 8-month DT program in 2016-2017. The program consisted of four 2-hour workshops with small group project work between sessions. In each session, resident teams shared their progress and analyzed emerging themes to solve well-being problems. At the conclusion of the program, they summarized the final design principles and recommendations that emerged from their work and were interviewed about DT as a strategy for developing well-being interventions for residents. OUTCOMES: Eighteen residents worked in teams to design solutions to improve: community and connection, space for reflection, peer support, and availability of individualized wellness. The resulting recommendations led to new interventions to improve well-being through near-peer communities. Residents emphasized how DT enhanced their creative thinking and trust in the residency program. They reported that not having enough time to work on projects between sessions and losing momentum during their clinical rotations were their biggest challenges. NEXT STEPS: Residents found DT useful for completing needs assessments, piloting interventions, and outlining essential design principles to improve well-being in residency. DT's focus on human values may be particularly suited to developing well-being interventions to enhance institutional community and culture. One outcome-that DT promoted creativity and trust for participants-may have applications in other spheres of medical education.

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment.

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

The International Incidence of Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding the epidemiology of traumatic brain injury (TBI) is essential to shape public health policy, implement prevention strategies, and justify allocation of resources toward research, education, and rehabilitation in TBI. There is not, to our knowledge, a systematic review of population-based studies addressing the epidemiology of TBI that includes all subtypes. We performed a comprehensive systematic review and meta-analysis of the worldwide incidence of TBI. METHODS: A search was conducted on May 23, 2014, in Medline and EMBASE according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Abstracts were screened independently and in duplicate to identify original research. Study quality and ascertainment bias were assessed in duplicate using a previously published tool. Demographic data and incidence estimates from each study were recorded, along with stratification by age, gender, year of data collection, and severity. RESULTS: The search strategy yielded 4944 citations. Two hundred and sixteen articles met criteria for full-text review; 144 were excluded. Hand searching resulted in ten additional articles. Eighty-two studies met all eligibility criteria. The pooled annual incidence proportion for all ages was 295 per 100,000 (95% confidence interval: 274-317). The pooled incidence rate for all ages was 349 (95% confidence interval: 96.2-1266) per 100,000 person-years. Incidence proportion and incidence rate were examined to see if associated with age, sex, country, or severity. CONCLUSIONS: We conclude that most TBIs are mild and most TBIs occur in males among the adult population. The incidence of TBI varies widely by ages and between countries. Despite being an important medical, economic, and social problem, the global epidemiology of TBI is still not well-characterized in the current literature. Understanding the incidence of TBI, particularly mild TBI, remains challenging because of nonstandardized reporting among neuroepidemiological studies.

Impact of wait times on spinal cord stimulation therapy outcomes.

OBJECTIVE: Presently, the long-term success rate of spinal cord stimulation (SCS) ranges from 47% to 74%. SCS efficacy is inversely proportional to the passage of time between development of chronic pain syndrome and time of implantation. To improve outcomes, implantation should be performed early. This study identifies sources of delay and offers suggestions for improvement. METHODS: A retrospective analysis of 437 SCS patients examines delays to accessing SCS at various points in the referral stream, from initial diagnosis, family physician, and various specialist treatments, to implantation. Analysis of variance evaluated the effect of age, sex, treating specialty, and their interactions on implantation delay. A multiple linear regression model was developed to assess factors contributing to implantation delay. RESULTS: From time of onset of chronic pain to implantation, patients endured a delay of 65.4 ± 2.04 months. Initial physician contact occurred at a mean of 3.4 ± 0.12 months after development of pain syndrome. Family physicians managed cases for 11.9 ± 0.45 months and various specialists for an additional 39.8 ± 1.22 months. Neurosurgeons were quickest to refer to an implant physician (average wait-time 32.28 ± 2.64 months), while orthopedic surgeons and nonimplanting anesthesiologists took the longest, contributing to wait times of 51.60 ± 5.04 months and 58.08 ± 5.76 months, respectively. Once the decision for implantation was made, the implanting physician required 3.31 ± 0.09 months to organize the procedure. A gradual decline in wait times was observed from 1980 to present. CONCLUSION: To improve SCS success rates, physicians involved in the treatment for chronic pain should refer these cases early to an implant physician once failure of medical management becomes apparent.

A comparative analysis of the results of vertebroplasty and kyphoplasty in osteoporotic vertebral compression fractures.

BACKGROUND: The most common complication of osteoporosis is vertebral fractures, which occur more frequently than all other fractures (hip, wrist, and ankle). OBJECTIVE: To prospectively analyze vertebroplasty compared with kyphoplasty for the treatment of osteoporotic vertebral compression fractures using improvement in pain, functional capacity, and quality of life as outcome measures. METHODS: The study population included 28 patients in the vertebroplasty group and 24 patients in the kyphoplasty group. The mean follow-up period was 42.2 weeks and 42.3 weeks in the vertebroplasty and kyphoplasty groups, respectively. Outcomes were measured pre- and postoperatively using the visual analogue scale, the Oswestry Disability Index, the EuroQol-5D questionnaire, and the Short-Form 36 Health Survey. RESULTS: In the vertebroplasty group, visual analogue scale scores improved from a mean of 8.0 cm to 5.5 cm at last follow-up (P = .001). Preoperatively, the Oswestry Disability Index was 57.6, which improved to 38.4 (P = .006). The EuroQol-5D score preoperatively was 0.157 and improved to 0.504 (P = .001). The Short-Form 36 Health Survey showed greatest improvement in the areas of physical health, role physical, body pain, and vitality. In the kyphoplasty group, visual analogue scale scores improved from a mean of 7.5 cm preoperatively to 2.5 cm postoperatively (P = .000001). The mean Oswestry Disability Index preoperatively was 50.7 and improved to 28.8 (P = .002). The EuroQol-5D score improved from a mean of 0.234 preoperatively to 0.749 (P = .00004). The Short-Form 36 Health Survey showed greatest improvement in the areas of physical health, physical functioning, role physical, body pain, and social functioning. CONCLUSION: Both vertebroplasty and kyphoplasty are effective at improving pain, functional disability, and quality of life; however, kyphoplasty provides better results, which are maintained over long-term follow-up.

[Injuries, accidents and mortality in epilepsy: a review of its prevalence risk factors and prevention]. / Lesiones, accidentes y mortalidad en epilepsia: Una revisión de sus prevalencias, factores de riesgo y prevención.

Currently, there is intense clinical research into various aspects of the medical risks relating to epilepsy, including total and cause-specific mortality, accidents and injuries in patients with epilepsy and mortality related with seizures. Submersion injuries, motor vehicle accidents, burns, and head injuries are among the most feared epilepsy-related injuries. Published risk factors for injuries include the number of antiepileptic drugs, history of generalized seizures, and seizure frequency. In general, studies focusing on populations with more severe forms of epilepsy tend to report substantially higher risks of injuries than those involving less selected populations. On the other hand, studies based in non selected populations of people with epilepsy have not shown an increase frequency of injuries in people with epilepsy compared with the general population. Some studies have shown that patients with epilepsy are more frequently admitted to the hospital following an injury. Possible explanations include are more cautious attitude of clinicians toward injuries occurring in the setting of seizures; hospitalization required because of seizures and not to the injuries themselves; and hospitalization driven by other issues, such as comorbidities, which are highly prevalent in patients with epilepsy. This article reviews information about specific type of injuries such as fractures, burns, concussions, dislocations, etc. Finally this article review in a comprehensive way information of mortality in patients with epilepsy. Aspects of mortality discussed in this review are: epidemiology, causes of mortality, sudden death in epilepsy and prevention measures.

Postpartum ovarian vein thrombosis: two cases and review of literature.

Introduction. We presented two cases of late presentation of ovarian vein thrombosis postpartum following vaginal delivery and cesarean section within a short period in our institution. Both of them had pelvic pain following their deliveries which was associated with fever and chills. One of them was quite a big-sized thrombophlebitic vein which was about 10 x 6 x 5 centimeters following a computed tomography. They were both treated initially for urinary tract infection, while a large ovarian vein thrombosis was not diagnosed in the second patient until her emergency department admission. Conclusion. Ovarian vein thrombosis is rare, but could present late, and difficult to diagnose, hence, should be considered as a differential diagnosis in a postpartum woman with fever and tender pelvic mass.

Injuries in epilepsy: a review of its prevalence, risk factors, type of injuries and prevention.

Currently, there is intense clinical research into various aspects of the medical risks relating to epilepsy, including total and cause-specific mortality, accidents and injuries in patients with epilepsy and mortality related with seizures. Seizures occurring in precarious situations and resulting in injuries are still an important concern for patients with epilepsy, their employers and their care-givers. Submersion injuries, motor vehicle accidents, burns, and head injuries are among the most feared epilepsy-related injuries. These concerns seem valid because the hallmark of epilepsy, episodic impairment of consciousness and motor control, may occur during interictal EEG epileptiform discharges, even in the absence of a clinical seizure. In addition, psychomotor comorbidity and side effects of antiepileptic drugs may contribute to the risk of injuries in patients with epilepsy. Published risk factors for injuries include the number of antiepileptic drugs, history of generalized seizures, and seizure frequency. In general, epidemiological information about incidence of injuries has been conflicting and sparse. In general, studies focusing on populations with more severe forms of epilepsy tend to report substantially higher risks of injuries than those involving less selected populations. On the other hand, studies based on non-selected populations of people with epilepsy have not shown an increased frequency of injuries in people with epilepsy compared with the general population. Some studies have shown that patients with epilepsy are more frequently admitted to the hospital following an injury. Possible explanations include: more cautious attitude of clinicians toward injuries occurring in the setting of seizures; hospitalization required because of seizures and not to the injuries themselves; and hospitalization driven by other issues, such as comorbidities, which are highly prevalent in patients with epilepsy. Potentially the high rate of hospitalizations could be related with the severity of the injury. This article reviews the best available epidemiological information about injuries, including incidence and risk factors. Also this article reviews information about specific types of injuries such as fractures, burns, concussions, dislocations, etc. Information about accidents in people with epilepsy is also discussed.