Transplanting neural progenitor cells to restore connectivity after spinal cord injury.

Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.

Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.

Hereditary spastic paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of human spastin gene (SPAST), which is the gene that encodes spastin, a microtubule-severing protein. The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies but not axonal swellings. On the other hand, mouse spastin gene (Spast)-knockout (KO) mice display axonal swellings but not corticospinal dieback or gait deficiencies. One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease but exacerbates the toxic effects of the mutant protein. To explore this idea, Spast-KO and hSPAST-C448Y mice were crossbred, and the offspring were compared with the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared with the hSPAST-C448Y mouse. These results, together with observations on changes in histone deacetylases 6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.

Spinal Interneurons as Gatekeepers to Neuroplasticity after Injury or Disease.

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.

Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse.

Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.

Diagnostic Accuracy of Synovial Lactate, Polymerase Chain Reaction, or Clinical Examination for Suspected Adult Septic Arthritis.

BACKGROUND: Adult septic arthritis can be challenging to differentiate from other causes of acute joint pain. The diagnostic accuracy of synovial lactate and polymerase chain reaction (PCR) remains uncertain. OBJECTIVE: Our aim was to quantify the diagnostic accuracy of synovial lactate, PCR, and clinical evaluation for adults with possible septic arthritis in the emergency department (ED). METHODS: We report a prospective sampling of ED patients aged ≥ 18 years with knee symptoms concerning for septic arthritis. Clinicians and research assistants independently performed history and physical examination. Serum and synovial laboratory testing was ordered at the discretion of the clinician. We analyzed frozen synovial fluid specimens for l- and d-lactate and PCR. The criterion standard for septic arthritis was bacterial growth on synovial culture and treated by consultants with operative drainage, prolonged antibiotics, or both. Diagnostic accuracy measures included sensitivity, specificity, likelihood ratios, interval likelihood ratios, and receiver operating characteristic area under the curve. RESULTS: Seventy-one patients were included with septic arthritis prevalence of 7%. No finding on history or physical examination accurately ruled in or ruled out septic arthritis. Synovial l- and d-lactate and PCR were inaccurate for the diagnosis of septic arthritis. Synovial white blood cell count and synovial Gram stain most accurately rule in and rule out septic arthritis. CONCLUSIONS: Septic arthritis prevalence in ED adults is lower than reported previously. History and physical examination, synovial lactate, and PCR are inadequate for the diagnosis of septic arthritis. Synovial white blood cell count and Gram stain are the most accurate tests available for septic arthritis.

How Do You Measure Up: Quality Measurement for Improving Patient Care and Establishing the Value of Infectious Diseases Specialists.

The shift from volume-based to value-based reimbursement has created a need for quantifying clinical performance of infectious diseases (ID) physicians. Nationally recognized ID specialty-specific quality measures will allow stakeholders, such as patients and payers, to determine the value of care provided by ID physicians and will promote clinical quality improvement. Few ID-specific measures have been developed; herein, we provide an overview of the importance of quality measurement for ID, discuss issues in quality measurement specific to ID, and describe standards by which candidate quality measures can be evaluated. If ID specialists recognize the need for quality measurement, then ID specialists can direct ID-related quality improvement, quantify the impact of ID physicians on patient outcomes, compare their performance to that of peers, and convey to stakeholders the value of the specialty.

Forelimb muscle plasticity following unilateral cervical spinal cord injury.

INTRODUCTION: Motor dysfunction and muscle atrophy are well documented in the lower extremity after spinal cord injury. However, the extent and time course of myoplastic changes in forelimb musculature is not clear. METHODS: Forelimb muscle morphology and fiber type were evaluated after high cervical hemilesion injury in rats. RESULTS: There was significant atrophy of the ipsilateral extensor carpi radialis longus (ECRL) muscle at 2 weeks postinjury, which was subsequently reversed at 8 weeks postinjury. The triceps muscle showed minimal evidence of atrophy after spinal injury. No significant changes in fiber type were observed. CONCLUSIONS: These findings indicate a robust capacity for spontaneous myoplasticity after C2 hemisection injury but highlight differential capacity for plasticity within the forelimb muscles.

Impact of Sepsis Classification and Multidrug-Resistance Status on Outcome Among Patients Treated With Appropriate Therapy.

OBJECTIVE: To assess the impact of sepsis classification and multidrug-resistance status on outcome in patients receiving appropriate initial antibiotic therapy. DESIGN: A retrospective cohort study. SETTING: Barnes-Jewish Hospital, a 1,250-bed teaching hospital. PATIENTS: Individuals with Enterobacteriaceae sepsis, severe sepsis, and septic shock who received appropriate initial antimicrobial therapy between June 2009 and December 2013. INTERVENTIONS: Clinical outcomes were compared according to multidrug-resistance status, sepsis classification, demographics, severity of illness, comorbidities, and antimicrobial treatment. MEASUREMENTS AND MAIN RESULTS: We identified 510 patients with Enterobacteriaceae bacteremia and sepsis, severe sepsis, or septic shock. Sixty-seven patients (13.1%) were nonsurvivors. Mortality increased significantly with increasing severity of sepsis (3.5%, 9.9%, and 28.6%, for sepsis, severe sepsis, and septic shock, respectively; p < 0.05). Time to antimicrobial therapy was not significantly associated with outcome. Acute Physiology and Chronic Health Evaluation II was more predictive of mortality than age-adjusted Charlson comorbidity index. Multidrug-resistance status did not result in excess mortality. Length of ICU and hospital stay increased with more severe sepsis. In multivariate logistic regression analysis, African-American race, sepsis severity, Acute Physiology and Chronic Health Evaluation II score, solid-organ cancer, cirrhosis, and transfer from an outside hospital were all predictors of mortality. CONCLUSIONS: Our results support sepsis severity, but not multidrug-resistance status as being an important predictor of death when all patients receive appropriate initial antibiotic therapy. Future sepsis trials should attempt to provide appropriate antimicrobial therapy and take sepsis severity into careful account when determining outcomes.

Perceptions and behaviours of infectious diseases physicians when managing urinary tract infections due to MDR organisms.

OBJECTIVES: The objective of this study was to attain a better understanding of infectious diseases (ID) physicians' experience with MDR organism (MDRO) urinary tract infections (UTIs) by means of a survey on disease perception, diagnostic management and treatment preferences. METHODS: A nine-question survey was developed and distributed to members of the North American Emerging Infections Network (EIN) in September 2013. RESULTS: Seven hundred and fourteen out of 1461 EIN members responded to the survey (49%). The responses of 603 responders were studied. Most providers perceived an increase in the incidence of MDRO UTIs over the past 3 years (75% of adult ID responders and 63% of paediatric ID responders). One hundred and thirty-four (22%) responders prefer intravenous over oral administration of antimicrobials when both are available, 171 (28%) prefer longer durations of therapy when comparing an MDRO with a susceptible isolate of the same species and 142 (24%) order a repeat urine culture as 'proof of cure' after treating an MDRO UTI. Nevertheless, 530 (88%) responders perceived MDRO UTIs to be of similar severity as non-MDRO UTIs. Fifty-five percent of providers prescribed fosfomycin for MDRO UTI at least once; the most common prescribing pattern (among a wide spectrum of approaches) was a single dose (16%). CONCLUSIONS: Future studies on MDRO UTIs should clarify the role of resistance in patient outcomes and the comparative efficacy of different antimicrobials. Of particular interest is fosfomycin, which is unrelated to other antibiotic classes and may take a more prominent role in treating MDRO cystitis.

Improving cervical cancer screening rates in an urban HIV clinic.

Human immunodeficiency virus (HIV)-infected women are at increased risk of invasive cervical cancer; however, screening rates remain low. The objectives of this study were to analyze a quality improvement intervention to increase cervical cancer screening rates in an urban academic HIV clinic and to identify factors associated with inadequate screening. Barriers to screening were identified by a multidisciplinary quality improvement committee at the Washington University Infectious Diseases clinic. Several strategies were developed to address these barriers. The years pre- and post-implementation were analyzed to examine the clinical impact of the intervention. A total of 422 women were seen in both the pre-implementation and post-implementation periods. In the pre-implementation period, 222 women (53%) underwent cervical cancer screening in the form of Papanicolaou (Pap) testing. In the post-implementation period, 318 women (75.3%) underwent cervical cancer screening (p < 0.01). Factors associated with lack of screening included fewer visits attended (pre: 4.2 ± 1.5; post: 3.4 ± 1.4; p < 0.01). A multidisciplinary quality improvement intervention was successful in overcoming barriers and increasing cervical cancer screening rates in an urban academic HIV clinic.

Challenges and Efficacy of Astrocyte-to-Neuron Reprogramming in Spinal Cord Injury: In Vitro Insights and In Vivo Outcomes.

Traumatic spinal cord injury (SCI) leads to the disruption of neural pathways, causing loss of neural cells, with subsequent reactive gliosis and tissue scarring that limit endogenous repair. One potential therapeutic strategy to address this is to target reactive scar-forming astrocytes with direct cellular reprogramming to convert them into neurons, by overexpression of neurogenic transcription factors. Here we used lentiviral constructs to overexpress Ascl1 or a combination of microRNAs (miRs) miR124, miR9/9*and NeuroD1 transfected into cultured and in vivo astrocytes. In vitro experiments revealed cortically-derived astrocytes display a higher efficiency (70%) of reprogramming to neurons than spinal cord-derived astrocytes. In a rat cervical SCI model, the same strategy induced only limited reprogramming of astrocytes. Delivery of reprogramming factors did not significantly affect patterns of breathing under baseline and hypoxic conditions, but significant differences in average diaphragm amplitude were seen in the reprogrammed groups during eupneic breathing, hypoxic, and hypercapnic challenges. These results show that while cellular reprogramming can be readily achieved in carefully controlled in vitro conditions, achieving a similar degree of successful reprogramming in vivo is challenging and may require additional steps.

Human spinal interneurons repair the injured spinal cord through synaptic integration.

Advances in cell therapy offer promise for some of the most devastating neural injuries, including spinal cord injury (SCI). Endogenous VSX2-expressing spinal V2a interneurons have been implicated as a key component in plasticity and therapeutically driven recovery post-SCI. While transplantation of generic V2a neurons may have therapeutic value, generation of human spinal V2a neurons with rostro-caudal specificity and assessment of their functional synaptic integration with the injured spinal cord has been elusive. Here, we efficiently differentiated optogenetically engineered cervical V2a spinal interneurons (SpINs) from human induced pluripotent stem cells and tested their capacity to form functional synapses with injured diaphragm motor networks in a clinically-relevant sub-acute model of cervical contusion injury. Neuroanatomical tracing and immunohistochemistry demonstrated transplant integration and synaptic connectivity with injured host tissue. Optogenetic activation of transplanted human V2a SpINs revealed functional synaptic connectivity to injured host circuits, culminating in improved diaphragm activity assessed by electromyography. Furthermore, optogenetic activation of host supraspinal pathways revealed functional innervation of transplanted cells by host neurons, which also led to enhanced diaphragm contraction indicative of a functional neuronal relay. Single cell analyses pre- and post-transplantation suggested the in vivo environment resulted in maturation of cervical SpINs that mediate the formation of neuronal relays, as well as differentiation of glial progenitors involved in repair of the damaged spinal cord. This study rigorously demonstrates feasibility of generating human cervical spinal V2a interneurons that develop functional host-transplant and transplant-host connectivity resulting in improved muscle activity post-SCI.

Outpatient Parenteral Antimicrobial Therapy in a Safety Net Hospital: Opportunities for Improvement.

Background: Outpatient parenteral antimicrobial therapy (OPAT) is a safe and cost-effective transitional care approach administered via different delivery models. No standards exist for appropriate OPAT program staffing. We examined outcomes of patients receiving OPAT via different care models to identify strategies to improve safety while reducing health care overuse. Methods: Retrospective demographic, clinical, and outcome data of patients discharged with OPAT were reviewed in 2 periods (April-June 2021 and January-March 2022; ie, when staffing changed) and stratified by care model: self-administered OPAT, health care OPAT, and skilled nursing facility OPAT. Results: Of 342 patients, 186 (54%) received OPAT in 2021 and 156 (46%) in 2022. Hospital length of stay rose from 12.4 days to 14.3 in 2022. In a Cox proportional hazards regression model, visits to the emergency department (ED) within 30 days of OPAT initiation (hazard ratio, 1.76; 95% CI, 1.13-2.73; P = .01) and readmissions (hazard ratio, 2.34; 95% CI, 1.22-4.49; P = .01) increased in 2022 vs 2021, corresponding to decreases in OPAT team staffing. Higher readmissions in the 2022 cohort were for reasons unrelated to OPAT (P = .01) while readmissions related to OPAT did not increase (P = .08). Conclusions: In a well-established OPAT program, greater health care utilization-length of stay, ED visits, and readmissions-were seen during periods of higher staff turnover and attrition. Rather than blunt metrics such as ED visits and readmissions, which are influenced by multiple factors besides OPAT, our findings suggest the need to develop OPAT-specific outcome measures as a quality assessment tool and to establish optimal OPAT program staffing ratios.

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation.

High spinal cord injuries (SCIs) lead to permanent functional deficits, including respiratory dysfunction. Patients living with such conditions often rely on ventilatory assistance to survive, and even those that can be weaned continue to suffer life-threatening impairments. There is currently no treatment for SCI that is capable of providing complete recovery of diaphragm activity and respiratory function. The diaphragm is the main inspiratory muscle, and its activity is controlled by phrenic motoneurons (phMNs) located in the cervical (C3-C5) spinal cord. Preserving and/or restoring phMN activity following a high SCI is essential for achieving voluntary control of breathing. In this review, we will highlight (1) the current knowledge of inflammatory and spontaneous pro-regenerative processes occurring after SCI, (2) key therapeutics developed to date, and (3) how these can be harnessed to drive respiratory recovery following SCIs. These therapeutic approaches are typically first developed and tested in relevant preclinical models, with some of them having been translated into clinical studies. A better understanding of inflammatory and pro-regenerative processes, as well as how they can be therapeutically manipulated, will be the key to achieving optimal functional recovery following SCIs.

Are cross-sectional safety climate survey results in operating room staff associated with the surgical site infection rates in Swiss hospitals?

OBJECTIVES: The aim of this study was to investigate the association between surgical site infections (SSIs), a major source of patient harm, and safety and teamwork climate. Prior research has been unclear regarding this relationship. DESIGN: Based on the Swiss national SSI surveillance and a survey study assessing (a) safety climate and (b) teamwork climate, associations were analysed for three kinds of surgical procedures. SETTING AND PARTICIPANTS: SSI surveillance data from 20 434 surgeries for hip and knee arthroplasty from 41 hospitals, 8321 for colorectal procedures from 28 hospitals and 4346 caesarean sections from 11 hospitals and survey responses from Swiss operating room personnel (N=2769) in 54 acute care hospitals. PRIMARY AND SECONDARY OUTCOMES: The primary endpoint of the study was the 30-day (all types) or 1-year (knee/hip with implants) National Healthcare Safety Network-adjusted SSI rate. Its association with climate level and strength was investigated in regression analyses, accounting for respondents' professional background, managerial role and hospital size as confounding factors. RESULTS: Plotting climate levels against infection rates revealed a general trend with SSI rate decreasing as the safety climate increased, but none of the associations were significant (5% level). Linear models for hip and knee arthroplasties showed a negative association between SSI rate and climate perception (p=0.02). For climate strength, there were no consistent patterns, indicating that alignment of perceptions was not associated with lower infection rates. Being in a managerial role and being a physician (vs a nurse) had a positive effect on climate levels regarding SSI in hip and knee arthroplasties, whereas larger hospital size had a negative effect. CONCLUSIONS: This study suggests a possible negative correlation between climate level and SSI rate, while for climate strength, no associations were found. Future research should study safety climate more specifically related to infection prevention measures to establish clearer links.

Preventing Surgical Site Infections: Are Safety Climate Level and Its Strength Associated With Self-reported Commitment To, Subjective Norms Toward, and Knowledge About Preventive Measures?

OBJECTIVES: Surgical site infections (SSIs) represent a major source of preventable patient harm. Safety climate in the operating room personnel is assumed to be an important factor, with scattered supporting evidence for the association between safety climate and infection outcome so far. This study investigated perceptions and knowledge specific to infection prevention measures and their associations with general assessments of safety climate level and strength. METHODS: We invited operating room personnel of hospitals participating in the Swiss SSI surveillance program to take a survey (response rate, 38%). A total of 2769 responses from 54 hospitals were analyzed. Two regression analyses were performed to identify associations between subjective norms toward, commitment to, as well as knowledge about prevention measures and safety climate level and strength, taking into account professional background and number of responses per hospital. RESULTS: Commitment to perform prevention measures even when situational pressures exist, as well as subjective norm of perceiving the expectation of others to perform prevention measures were significantly ( P < 0.05) related to safety climate level, while for knowledge about preventative measures this was not the case. None of the assessed factors was significantly associated with safety climate strength. CONCLUSIONS: While pertinent knowledge did not have a significant impact, the commitment and the social norms to maintain SSI prevention activities even in the face of other situational demands showed a strong influence on safety climate. Assessing the knowledge about measures to prevent SSIs in operating room personnel opens up opportunities for designing intervention efforts in reducing SSIs.

Paragonimus kellicotti flukes in Missouri, USA.

Paragonimiasis is an infection caused by lung flukes of the genus Paragonimus. In Asia, P. westermani infections are relatively common because of dietary practices. However, in North America, cases of paragonimiasis, which are caused by P. kellicotti flukes, are rare. Only 7 autochthonous cases of paragonimiasis were reported during 1968-2008. In 2009, we reported 3 new case-patients with paragonimiasis who had been seen at our medical center over an 18-month period. Six additional case-patients were identified in St. Louis, Missouri, USA, and treated at Washington University-affiliated health centers in 2009-2010. We report detailed descriptions of these case-patients, which includes unusual clinical manifestations. We also describe public health interventions that were undertaken to inform the general public and physicians about the disease and its mode of transmission.

Chest CT features of North American paragonimiasis.

OBJECTIVE: The purpose of this study was to characterize the chest CT findings of North American paragonimiasis due to Paragonimus kellicotti in the largest (to our knowledge) case series reported to date and to compare the findings with those reported for paragonimiasis infections in other regions. MATERIALS AND METHODS: A retrospective review was performed of chest CT examinations of eight patients with North American paragonimiasis treated at our institution between 2006 and 2010. Findings were characterized by site of involvement, including lungs and pleura, heart and pericardium, lymph nodes, and upper abdomen. RESULTS: The most common chest CT findings in this case series were pleural effusions and internal mammary and cardiophrenic lymphadenopathy. Pulmonary parenchymal findings included peripheral lung nodules of 1-3.5 cm in size with surrounding ground-glass opacity; many nodules had a linear track to the pleural surface that may correspond to the worm's burrow tunnel. Pericardial involvement (5/8 patients) and omental inflammation (5/7 patients), which are uncommon in Asian paragonimiasis, were common in this series. CONCLUSION: Pleural and pulmonary features of North American paragonimiasis are generally similar to those reported from Asia. The presence of a track between a pulmonary nodule and the pleura may help distinguish paragonimiasis from mimickers, including chronic eosinophilic pneumonia, tuberculosis, fungal infection, or malignancy. Pericarditis, lymphadenopathy, and omental inflammation were more common in our series than in reports on paragonimiasis from other regions. These differences may be related to the infecting parasite species or to the fact that radiologic examinations in the present series were performed relatively early in the course of infection.