Epidural electrical stimulation of the cervical spinal cord opposes opioid-induced respiratory depression.

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid-induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF-State) or partial suppression (ON-State) of respiration induced by remifentanil. During the ON-State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end-tidal carbon dioxide level compared to pre-stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre-stimulation control levels. In the OFF-State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non-responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. KEY POINTS: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA-approved method to manage chronic pain. We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low-dose remifentanil that suppressed respiration (ON-State) or high-dose remifentanil that completely inhibited breathing (OFF-State) during the course of cervical surgery. Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2-C7). Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF-State, suggesting that cervical EES reversed the opioid-induced respiratory depression. These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids.

Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening.

Characterizing the immune response to pneumococcal proteins is critical in understanding this bacterium's epidemiology and vaccinology. Probing a custom-designed proteome microarray with sera from 35 healthy US adults revealed a continuous distribution of IgG affinities for 2,190 potential antigens from the species-wide pangenome. Reproducibly elevated IgG binding was elicited by 208 "antibody binding targets" (ABTs), which included 109 variants of the diverse pneumococcal surface proteins A and C (PspA and PspC) and zinc metalloprotease A and B (ZmpA and ZmpB) proteins. Functional analysis found ABTs were enriched in motifs for secretion and cell surface association, with extensive representation of cell wall synthesis machinery, adhesins, transporter solute-binding proteins, and degradative enzymes. ABTs were associated with stronger evidence for evolving under positive selection, although this varied between functional categories, as did rates of diversification through recombination. Particularly rapid variation was observed at some immunogenic accessory loci, including a phage protein and a phase-variable glycosyltransferase ubiquitous among the diverse set of genomic islands encoding the serine-rich PsrP glycoprotein. Nevertheless, many antigens were conserved in the core genome, and strains' antigenic profiles were generally stable. No strong evidence was found for any epistasis between antigens driving population dynamics, or redundancy between functionally similar accessory ABTs, or age stratification of antigen profiles. These results highlight the paradox of why substantial variation is observed in only a subset of epitopes. This result may indicate only some interactions between immunoglobulins and ABTs clear pneumococcal colonization or that acquired immunity to pneumococci is an accumulation of individually weak responses to ABTs evolving under different levels of functional constraint.

Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci.

Streptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals' responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins' ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts' polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.

Synthesis of Long COVID Symptoms: An Evidence-Based Standardized Mapping Study With the Omaha System.

Background: In COVID-19 survivors, symptom burden is a significant and multifaceted personal and societal challenge. The Omaha system is a standardized terminology used by researchers and clinicians for documentation and analysis of meaningful data for whole-person health. Given the urgent need for a standardized symptom checklist specific to the long COVID population, the purpose of the present study was to identify long COVID symptoms from the published literature (native symptoms) and map those to the Omaha system signs/symptoms terms. Methods: The long COVID symptoms identified from 13 literatures were mapped to the Omaha system signs/symptoms, using an expert consensus approach. The criteria for mapping were that the long COVID signs/symptoms had to contain either a one-to-one match (exact meaning of the native terms and the signs/symptoms) or a partial match (similar but not exact meaning). Results: The synthesis of the 217 native symptoms of long COVID and mapping analysis to the Omaha problems and signs/symptoms level resulted in a combined, deduplicated, and standardized list of 74 signs/symptoms for 23 problems. Of these, 72 (97.3%) of native signs/symptoms were a full match at the problem level, and 67 (90.5%) of native signs/symptoms were a full or partial match at the sign/symptoms level. Conclusions: The present study is the first step in identifying a standardized evidence-based symptom checklist for long COVID patients. This checklist may be used in practice and research for assessment, tracking, and intervention planning as well as longitudinal analysis of symptom resolution and intervention effectiveness.

Preexisting anticoagulation is an independent predictor of mortality in geriatric trauma patients - a retrospective cohort study.

Introduction: Preexisting anticoagulation is common among geriatric trauma patients. Geriatric trauma patients have a higher risk of mortality compared to younger patients. We sought to evaluate the association of preexisting anticoagulation with mortality in a group of geriatric trauma patients. Methods: A retrospective review of geriatric trauma patients was conducted for those admitted to a Level 1 trauma center from January 2018 to December 2020. Vital signs, demographics, injury characteristics, laboratory data, and mortality were all collected. Multivariable logistic regression analysis was performed for the association of preexisting anticoagulation and a primary endpoint of all-cause mortality. These groups were controlled for preexisting comorbidities, injury severity scores, and systolic blood pressure in the emergency department. Results: Four thousand four hundred thirty-two geriatric patients were admitted during the study period. This cohort was made up of 36.9% men and 63.1% women. Three thousand eight hundred fifty-nine (87.2%) were white; the average age was 81±8.5 years, and the median injury severity score (ISS) was 5. The mean systolic blood pressure was 150±32 mmHg, mean heart rate was 81±16 bpm, mean lactate was 2.3±1.3, mean hematocrit was 37.3±8.8, and mean international normalized ratio (INR) was 1.7±10.3. One thousand five hundred ninety-two (35.9%) patients were on anticoagulation (AC) upon presentation. One hundred and sixty-five (3.7%) mortalities were recorded. Multivariable logistic regression analysis results show that preexisting anticoagulation [ odds ratio (OR) 1.92, 95% CI 1.36-2.72] was independently predictive of death. The analysis was adjusted for systolic BP in the emergency department less than90 mmHg (OR 5.55, 95% CI 2.83-10.9), having more than 1 comorbidity (OR 2.30, 95% CI 1.57-3.38) and ISS (OR 1.13, 95% CI 1.10-1.15). Conclusion: Our study indicates that preexisting anticoagulation is associated with mortality among geriatric trauma patients.

Management of aortic occlusion in a morbidly obese smoker: A case report.

Total occlusion of the abdominal aorta is a rare and life-threatening event. Risk factors most commonly include coagulopathy, vasculitis, trauma, abdominal aortic aneurysms, aortic thromboembolism, and aortic dissection. The most common complications include severe ischemic manifestations in the lower extremities, spinal cord, or viscera. Thus, management is largely dependent on presumed etiology. We present a case of a morbidly obese 52-year-old female with a past medical history of hypertension, diabetes mellitus, peripheral vascular disease, and coronary artery disease with a smoking history of three packs per day for over 10 years. The patient first presented to our emergency department with bilateral lower extremity paresthesia and pain at rest. Further evaluation through computed tomography angiogram thus revealed infrarenal occlusion of the abdominal aorta and bilateral common iliac arteries; the patient was treated with an aorto-femoral bypass without further sequelae. Our case report details the associated risk factors of acute on chronic aortic occlusion and its management.

Factors Predictive of Mortality among Geriatric Patients Sustaining Low-Energy Blunt Trauma.

Background: In geriatric trauma patients, higher mortality rate is observed compared to younger patients. A significant portion of trauma sustained by this age group comes from low-energy mechanisms (fall from standing or sitting). We sought to investigate the outcome of these patients and identify factors associated with mortality. Methods: A retrospective review of 1285 geriatric trauma patients who came to our level 1 trauma center for trauma activation (hospital alert to mobilize surgical trauma service, emergency department trauma team, nursing, and ancillary staff for highest level of critical care) after sustaining low-energy blunt trauma over a 1-year period. IRB approval was obtained, data collected included demographics, vital signs, laboratory data, injuries sustained, length of stay and outcomes. Patients were divided into three age categories: 65−74, 75−84 and >85. Comorbidities collected included a history of chronic renal failure, COPD, Hypertension and Myocardial Infarction. Results: 1285 geriatric patients (age > 65 years) presented to our level 1 trauma center for trauma activation with a low-energy blunt trauma during the study period; 34.8% of the patients were men, 20.5% had at least one comorbidity, and 89.6% were white. Median LOS was 5 days; 37 (2.9%) patients died. Age of 85 and over (OR 3.44 with 95% CI 1.01−11.7 and 2.85 with 95% CI 1.0−6.76, when compared to 65−74 and 75−84, respectively), injury severity score (ISS) (OR 1.08, 95% CI 1.02 to 1.15) and the presence of more than one comorbidity (OR 2.68, 95% CI 1.26 to 5.68) were independently predictive of death on multi-variable logistic regression analysis. Conclusion: Age more than 85 years, higher injury severity score and the presence of more than one comorbidity are independent predictors of mortality among geriatric patients presenting with low-energy blunt trauma.

The Association of Gender and Mortality in Geriatric Trauma Patients.

The association of gender with mortality in trauma remains a subject of debate. Geriatric trauma patients have a higher risk of mortality compared to younger patients. We sought to evaluate the association of gender with mortality in a group of geriatric trauma patients presenting to an academic level 1 trauma center (trauma center designated by New York State capable of handling the most severe injuries and most complex cases). METHODS: We performed a retrospective review of geriatric trauma patients who were admitted to our trauma center between January 2018 and December 2020. Data collected included vital signs, demographics, injury, and clinical characteristics, laboratory data and outcome measures. The study controlled for co-morbidities, injury severity score (ISS), and systolic blood pressure (SBP) in the ED. Multivariable logistic regression analysis was performed to evaluate the association of gender and mortality. RESULTS: 4432 geriatric patients were admitted during the study period, there were 1635 (36.9%) men and 3859 (87.2%) were White with an average age of 81 ± 8.5 years. The mean ISS was 6.7 ± 5.4 and average length of stay was 6 ± 6.3 days. There were 165 deaths. Male gender (OR 1.94, 95% CI 1.38 to 2.73), ISS (OR 1.12, 95% CI 1.09 to 1.14), Emergency Department SBP less than 90 mmHg (OR 6.17, 95% CI 3.17 to 12.01), and having more than one co-morbidity (OR 2.28, 95% CI 1.55 to 3.35) were independently predictive of death on multivariable logistic regression analysis. CONCLUSION: Male gender, Emergency Department systolic blood pressure less than 90 mmHg, having more than one co-morbidity, and injury severity are independent predictors of mortality among geriatric trauma patients.

Minimal handgrip force is needed for transcutaneous electrical stimulation to improve hand functions of patients with severe spinal cord injury.

Spinal cord stimulation enhanced restoration of motor function following spinal cord injury (SCI) in unblinded studies. To determine whether training combined with transcutaneous electrical spinal cord stimulation (tSCS), with or without systemic serotonergic treatment with buspirone (busp), could improve hand function in individuals with severe hand paralysis following SCI, we assessed ten subjects in a double-blind, sham-controlled, crossover study. All treatments-busp, tSCS, and the busp plus tSCS-reduced muscle tone and spasm frequency. Buspirone did not have any discernible impact on grip force or manual dexterity when administered alone or in combination with tSCS. In contrast, grip force, sinusoidal force generation and grip-release rate improved significantly after 6 weeks of tSCS in 5 out of 10 subjects who had residual grip force within the range of 0.1-1.5 N at the baseline evaluation. Improved hand function was sustained in subjects with residual grip force 2-5 months after the tSCS and buspirone treatment. We conclude that tSCS combined with training improves hand strength and manual dexterity in subjects with SCI who have residual grip strength greater than 0.1 N. Buspirone did not significantly improve the hand function nor add to the effect of stimulation.

Proteome-wide analysis of a malaria vaccine study reveals personalized humoral immune profiles in Tanzanian adults.

Tanzanian adult male volunteers were immunized by direct venous inoculation with radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (PfSPZ Vaccine) and protective efficacy assessed by homologous controlled human malaria infection (CHMI). Serum immunoglobulin G (IgG) responses were analyzed longitudinally using a Pf protein microarray covering 91% of the proteome, providing first insights into naturally acquired and PfSPZ Vaccine-induced whole parasite antibody profiles in malaria pre-exposed Africans. Immunoreactivity was identified against 2239 functionally diverse Pf proteins, showing a wide breadth of humoral response. Antibody-based immune 'fingerprints' in these individuals indicated a strong person-specific immune response at baseline, with little changes in the overall humoral immunoreactivity pattern measured after immunization. The moderate increase in immunogenicity following immunization and the extensive and variable breadth of humoral immune response observed in the volunteers at baseline suggest that pre-exposure reduces vaccine-induced antigen reactivity in unanticipated ways.

Naturally acquired immunity against immature Plasmodium falciparum gametocytes.

The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention.

Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination.

Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody 'fingerprints', responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV's surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding to a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity.Clinical trial registration: The trial was registered with ClinicalTrials.gov with Identifier NCT01537185; the results are available from https://clinicaltrials.gov/ct2/show/results/NCT01537185.