Outcomes, complications, and dosing of intrathecal baclofen in the treatment of multiple sclerosis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate empirical outcomes of studies in the literature that investigated effectiveness of intrathecal baclofen (ITB) in the treatment of multiple sclerosis (MS)-related spasticity (MSRS) based on various metrics. Since the first description of this route of baclofen delivery for MS patients by Penn and Kroin in 1984, numerous studies have contributed to the medical community's knowledge of this treatment modality. The authors sought to add to the literature a systematic review of studies over the last 2 decades that elucidates the clinical impact of ITB in treating MSRS with the following endpoints: impact on patient-centered outcomes, such as spasticity reduction (primary), complications (secondary), and dosing (secondary). METHODS: The authors queried three databases (PubMed, Scopus, and Cochrane Library) using the following search terms: (intrathecal baclofen) AND (multiple sclerosis). The set inclusion criteria were as follows: 1) original, full-text article; 2) written in the English language; 3) published between and including the years 2000 and 2023; 4) discussion of pre- and post-ITB pump implantation outcomes (e.g., reduction in spasticity and improved comfort) in MSRS patients with long-term ITB treatment; and 5) contained a minimum of 5 MS patients. Data on study type, patient demographics, follow-up periods, primary outcomes, and secondary outcomes were extracted from the included studies. RESULTS: The authors' search yielded 465 studies, of which 17 met inclusion criteria. Overall, they found evidence for the effectiveness of ITB in treating MSRS patients whose condition was refractory to oral medications, with significant reported changes in spasm frequency from pre- to postimplantation. They also found evidence supporting the positive impact of ITB on MSRS patients' quality of life. Moreover, the authors found that most complications were surgical rather than pharmacological. In addition, the average 1-year dose of ITB (reported in 7 of the included studies) was 191.93 µg/day, which is substantially lower than ITB doses reported in the literature for patients with central (non-MS) or spinal origins of spasticity at 1-year follow-up. CONCLUSIONS: The evidence supports ITB as a clinically effective treatment for MSRS, particularly in patients in whom oral antispasmodics and physiotherapy have failed. This systematic review contributes a comprehensive synthesis of clinical benefits, complications, and dosing of ITB reported over the past 2 decades, which furthers an understanding of ITB's clinical utility in practice.

Middle Meningeal Artery Embolization in Pediatric Patients.

BACKGROUND: Middle meningeal artery (MMA) embolization has been increasingly applied in adult populations for the treatment of chronic subdural hematomas (cSDH). There is a paucity of literature on the indications, safety, and outcomes of MMA embolization in the pediatric population. SUMMARY: A systematic literature review on pediatric patients undergoing MMA embolization was performed. We also report the case of successful bilateral MMA embolization for persistent subdural hematomas following resection of a juvenile pilocytic astrocytoma. Persistent bilateral subdural hematomas following resection of a large brain tumor resolved following MMA embolization in a 13-year-old male. Indications for MMA embolization in the pediatric literature included cSDH (6/13, 46.2%), treatment or preoperative embolization of arteriovenous fistula or arteriovenous malformation (3/13, 23.1%), preoperative embolization for tumor resection (1/13, 7.7%), or treatment of acute epidural hematoma (1/13, 7.7%). Embolic agents included microspheres or microparticles (2/13, 15.4%), Onyx (3/13, 23.1%), NBCA (3/13, 23.1%), or coils (4/13, 30.8%). KEY MESSAGES: Whereas MMA embolization has primarily been applied in the adult population for subdural hematoma in the setting of cardiac disease and anticoagulant use, we present a novel application of MMA embolization in the management of persistent subdural hematoma following resection of a large space-occupying lesion. A systematic review of MMA embolization in pediatric patients currently shows efficacy; a multi-institutional study is warranted to further refine indications, timing, and safety of the procedure.

Myasthenia gravis in a pediatric patient with Lennox-Gastaut syndrome following responsive neurostimulation device implantation: illustrative case.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder in which the postsynaptic acetylcholine receptor of the neuromuscular junction is destroyed by autoantibodies. The authors report a case of MG in a pediatric patient who also suffered from Lennox-Gastaut syndrome (LGS) and is one of a limited number of pediatric patients who have undergone placement of a responsive neurostimulation (RNS) device (NeuroPace). OBSERVATIONS: A 17-year-old female underwent placement of an RNS device for drug-resistant epilepsy in the setting of LGS. Five months after device placement, the patient began experiencing intermittent slurred speech, fatigue, and muscle weakness. Initially, the symptoms were attributed to increased seizure activity and/or medication side effects. However, despite changing medications and RNS settings, no improvements occurred. Her antiacetylcholine receptor antibodies measured 62.50 nmol/L, consistent with a diagnosis of MG. The patient was then prescribed pyridostigmine and underwent a thymectomy, which alleviated most of her symptoms. LESSONS: The authors share the cautionary tale of a case of MG in a pediatric patient who was treated with RNS for intractable epilepsy associated with LGS. Although slurred speech, fatigue, muscle weakness, and other symptoms might stem from increased seizure activity and/or medication side effects, they could also be due to MG development.

Moving upstream: healthcare partnerships addressing social determinants of health through community wealth building.

BACKGROUND: Healthcare-based interventions addressing social needs such as food and housing generally fail to impact the upstream wealth and power inequities underlying those needs. However, a small number of US healthcare organizations have begun addressing these upstream inequities by partnering with community wealth building initiatives. These initiatives include community land trusts, resident-owned communities, and worker cooperatives, which provide local residents ownership and control over their housing and workplaces. While these partnerships represent a novel, upstream approach to the social determinants of health, no research has yet evaluated them. METHODS: To assess the current state and key aspects of healthcare-community wealth building partnerships, we conducted a multiple case study analysis using semi-structured interviews with thirty-eight key informants across ten partnerships identified through the Healthcare Anchor Network. To analyze the interviews, we used a two-stage coding process. First, we coded responses based on the phase of the intervention to which they corresponded: motivation, initiation, implementation, or evaluation. Then we assessed responses within each aspect for common themes and variation on salient topics. RESULTS: Partnerships were generally motivated by a combination of community needs, such as affordable housing and living wage jobs, and health system interests, such as workforce housing and supply chain resilience. Initiating projects required identifying external partners, educating leadership, and utilizing risk mitigation strategies to obtain health system buy-in. Implementation took various forms, with healthcare organizations providing financial capital in the form of grants and loans, social capital in the form of convening funders and other stakeholders, and/or capacity building support in the form of strategic planning or technical assistance resources. To evaluate projects, healthcare organizations used more process and community-level metrics rather than metrics based on individual health outcomes or returns on investment. Based on best practices from each partnership phase, we provide a roadmap for healthcare organizations to develop effective community wealth building partnerships. CONCLUSIONS: Assessing healthcare partnerships with community wealth building organizations yields key strategies healthcare organizations can use to develop more effective partnerships to address the upstream causes of poor health.

Intraoperative Nerve Stimulation as an Approach for the Surgical Treatment of Genitofemoral Neuralgia.

BACKGROUND Genitofemoral neuralgia is a pain syndrome that involves injury to the genitofemoral nerve and is frequently iatrogenic. We report intraoperative nerve localization using ultrasound, nerve stimulation, and the cremasteric reflex in the surgical treatment of genitofemoral neuralgia. CASE REPORT A 49-year-old man with a history of extracorporeal membrane oxygenation with cannulation sites in bilateral inguinal regions presented with right groin numbness and pain following decannulation. His symptoms corresponded to the distribution of the genitofemoral nerve. He had a Tinel's sign over the midpoint of his inguinal incision. A nerve block resulted in temporary resolution of his symptoms. Due to the presence of a pacemaker, peripheral nerve neuromodulation was contraindicated. He underwent external neurolysis and neurectomy of the right genitofemoral nerve. Following direct stimulation and ultrasound for localization, the nerve was further localized intraoperatively using nerve stimulation with monitoring for the presence of the cremasteric reflex. At his 1-month postoperative visit, his right medial thigh pain had resolved and his right testicular pain 50% improved; his residual pain continued to improve at last evaluation 3 months after surgery. CONCLUSIONS We report the successful use of nerve stimulation and the cremasteric reflex to aid in identification of the genitofemoral nerve intraoperatively for the treatment of genitofemoral neuralgia.

More than a feeling: Scalp EEG and eye signals in conscious tactile perception.

Understanding the neural basis of consciousness is a fundamental goal of neuroscience, and sensory perception is often used as a proxy for consciousness in empirical studies. However, most studies rely on reported perception of visual stimuli. Here we present behavior, high density scalp EEG and eye metric recordings collected simultaneously during a novel tactile threshold perception task. We found significant N80, N140 and P300 event related potentials in perceived trials and in perceived versus not perceived trials. Significance was limited to a P100 and P300 in not perceived trials. We also found an increase in pupil diameter and blink rate and a decrease in microsaccade rate following perceived relative to not perceived tactile stimuli. These findings support the use of eye metrics as a measure of physiological arousal associated with conscious perception. Eye metrics may also represent a novel path toward the creation of tactile no-report tasks in the future.

COVID-19 interventional trials: Analysis of data sharing intentions during a time of pandemic.

BACKGROUND: This survey of COVID-19 interventional studies encompasses, and expands upon, a previous publication [1] examining individual participant level data (IPD) sharing intentions for COVID-related trials and publications prior to June 30, 2020. METHODS: Replicating our inclusion criteria from the original survey, we evaluated a larger dataset of 2759 trials and 281 publications in this follow-up survey for willingness to share IPD and studied if sharing sentiment has evolved since the beginning of the pandemic. RESULTS: We found that 18 months into the pandemic, data sharing intentions remained static at 15% for trials registered through ClinicalTrials.gov (ClinicalTrials.gov is a digital registry of information about publicly and privately funded clinical studies in which human volunteers participate in interventional or observational scientific research) prior to September 19, 2021 compared to our initial survey. However, a comparison of declared intentions to share IPD at the time of publication revealed a noticeable shift: affirmative intentions grew from 21.4% (6/28) in our original publications survey to 57% (160/281) in this survey. Within the subset of studies published within journals affiliated with the International Committee of Medical Journal Editors (ICMJE), positive sharing intentions are even higher (65%). CONCLUSIONS: Although intent to share data at the time of registration has not changed from our prior study in June 2020, there is growing commitment to sharing data reflected in the increasing number of affirmative declarations at the time of publication. Actual sharing of data will accelerate new insights into COVID-19 through secondary re-use of data.

Traumatic Brain Injury: What Is a Favorable Outcome?

Traumatic brain injury (TBI) results in disparate outcomes ranging from persistent disorders of consciousness to symptom resolution. Despite the breadth and complexity of TBI recovery, most clinical trials dichotomize outcome by establishing an arbitrary cut-point, above and below which recovery is described as "favorable" and "unfavorable," respectively. For example, the widely used eight-level Glasgow Outcome Scale-Extended (GOSE) is typically collapsed into these two categories. Dichotomizing the GOSE into "favorable" and "unfavorable" outcome may limit detection of treatment effects in TBI clinical trials, contribute to imprecise prognostic counseling, and unduly influence decision-making with regard to withdrawal of life-sustaining therapy. We illustrate the lack of standardization in defining "unfavorable" and "favorable" TBI outcome on the GOSE by identifying the broad range of cut-points, from a score of 3 (part-time supervision in the home required) to 7 (presence of some residual of symptoms), that have been used to dichotomize the GOSE. We also highlight the ethical concerns related to characterizing TBI outcomes solely from the perspective of investigators and clinicians, rather than patients and caregivers. Finally, we suggest that a pragmatic, immediate solution to GOSE dichotomization is to report the likelihood of achieving each of the eight GOSE outcome levels and propose a study design for a new patient- and caregiver-centered TBI outcome metric.

Building Community Well-being by Leveraging the Economic Impact of Health Systems.

Local communities face systematically deepening disparities in economic, health, and well-being outcomes. Nurses are increasingly leading initiatives to positively impact the social determinants of health in local communities. This article describes how to use the enormous economic impact of hospitals and health systems as anchor institutions embedded in local communities. By leveraging the everyday business practices of hospitals and health systems, such as hiring, purchasing, and investing, nurses can help to transform the economic and consequent health well-being of socioeconomically disadvantaged individuals and neighborhoods. Hiring, purchasing, and investing in nearby neighborhoods build community wealth through both gainful employment and subsequent recirculation of money locally. Improving the economic viability of the local community positively impacts concomitant social determinants of health. Nurses, with their experience and expertise in collaboration and communication with diverse stakeholder and with their high ranking as the most trusted profession, are natural leaders to build community networks and partnerships that promote community transformation for well-being.

Up and Down States of Cortical Neurons in Focal Limbic Seizures.

Recent work suggests an important role for cortical-subcortical networks in seizure-related loss of consciousness. Temporal lobe seizures disrupt subcortical arousal systems, which may lead to depressed cortical function and loss of consciousness. Extracellular recordings show ictal neocortical slow waves at about 1 Hz, but it is not known whether these simply represent seizure propagation or alternatively deep sleep-like activity, which should include cortical neuronal Up and Down states. In this study, using in vivo whole-cell recordings in a rat model of focal limbic seizures, we directly examine the electrophysiological properties of cortical neurons during seizures and deep anesthesia. We found that during seizures, the membrane potential of frontal cortical secondary motor cortex layer 5 neurons fluctuates between Up and Down states, with decreased input resistance and increased firing rate in Up states when compared to Down states. Importantly, Up and Down states in seizures are not significantly different from those in deep anesthesia, in terms of membrane potential, oscillation frequency, firing rate, and input resistance. By demonstrating these fundamental similarities in cortical electrophysiology between deep anesthesia and seizures, our results support the idea that a state of decreased cortical arousal may contribute to mechanisms of loss of consciousness during seizures.

Cell rejuvenation and social behaviors promoted by LPS exchange in myxobacteria.

Bacterial cells in their native environments must cope with factors that compromise the integrity of the cell. The mechanisms of coping with damage in a social or multicellular context are poorly understood. Here we investigated how a model social bacterium, Myxococcus xanthus, approaches this problem. We focused on the social behavior of outer membrane exchange (OME), in which cells transiently fuse and exchange their outer membrane (OM) contents. This behavior requires TraA, a homophilic cell surface receptor that identifies kin based on similarities in a polymorphic region, and the TraB cohort protein. As observed by electron microscopy, TraAB overexpression catalyzed a prefusion OM junction between cells. We then showed that damage sustained by the OM of one population was repaired by OME with a healthy population. Specifically, LPS mutants that were defective in motility and sporulation were rescued by OME with healthy donors. In addition, a mutant with a conditional lethal mutation in lpxC, an essential gene required for lipid A biosynthesis, was rescued by Tra-dependent interactions with a healthy population. Furthermore, lpxC cells with damaged OMs, which were more susceptible to antibiotics, had resistance conferred to them by OME with healthy donors. We also show that OME has beneficial fitness consequences to all cells. Here, in merged populations of damaged and healthy cells, OME catalyzed a dilution of OM damage, increasing developmental sporulation outcomes of the combined population by allowing it to reach a threshold density. We propose that OME is a mechanism that myxobacteria use to overcome cell damage and to transition to a multicellular organism.

The bactofilin cytoskeleton protein BacM of Myxococcus xanthus forms an extended ß-sheet structure likely mediated by hydrophobic interactions.

Bactofilins are novel cytoskeleton proteins that are widespread in Gram-negative bacteria. Myxococcus xanthus, an important predatory soil bacterium, possesses four bactofilins of which one, BacM (Mxan_7475) plays an important role in cell shape maintenance. Electron and fluorescence light microscopy, as well as studies using over-expressed, purified BacM, indicate that this protein polymerizes in vivo and in vitro into ~3 nm wide filaments that further associate into higher ordered fibers of about 10 nm. Here we use a multipronged approach combining secondary structure determination, molecular modeling, biochemistry, and genetics to identify and characterize critical molecular elements that enable BacM to polymerize. Our results indicate that the bactofilin-determining domain DUF583 folds into an extended ß-sheet structure, and we hypothesize a left-handed ß-helix with polymerization into 3 nm filaments primarily via patches of hydrophobic amino acid residues. These patches form the interface allowing head-to-tail polymerization during filament formation. Biochemical analyses of these processes show that folding and polymerization occur across a wide variety of conditions and even in the presence of chaotropic agents such as one molar urea. Together, these data suggest that bactofilins are comprised of a structure unique to cytoskeleton proteins, which enables robust polymerization.

Three basic residues of intracellular loop 3 of the beta-1 adrenergic receptor are required for golgin-160-dependent trafficking.

Golgin-160 is a member of the golgin family of proteins, which have been implicated in the maintenance of Golgi structure and in vesicle tethering. Golgin-160 is atypical; it promotes post-Golgi trafficking of specific cargo proteins, including the ß-1 adrenergic receptor (ß1AR), a G protein-coupled receptor. Here we show that golgin-160 binds directly to the third intracellular loop of ß1AR and that this binding depends on three basic residues in this loop. Mutation of the basic residues does not affect trafficking of ß1AR from the endoplasmic reticulum through the Golgi complex, but results in reduced steady-state levels at the plasma membrane. We hypothesize that golgin-160 promotes incorporation of ß1AR into specific transport carriers at the trans-Golgi network to ensure efficient delivery to the cell surface. These results add to our understanding of the biogenesis of ß1AR, and suggest a novel point of regulation for its delivery to the plasma membrane.

Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication.

BACKGROUND: Infectious bronchitis virus (IBV) is a pathogenic chicken coronavirus. Currently, vaccination against IBV is only partially protective; therefore, better preventions and treatments are needed. Plants produce antimicrobial secondary compounds, which may be a source for novel anti-viral drugs. Non-cytotoxic, crude ethanol extracts of Rhodiola rosea roots, Nigella sativa seeds, and Sambucus nigra fruit were tested for anti-IBV activity, since these safe, widely used plant tissues contain polyphenol derivatives that inhibit other viruses. RESULTS: Dose-response cytotoxicity curves on Vero cells using trypan blue staining determined the highest non-cytotoxic concentrations of each plant extract. To screen for IBV inhibition, cells and virus were pretreated with extracts, followed by infection in the presence of extract. Viral cytopathic effect was assessed visually following an additional 24 h incubation with extract. Cells and supernatants were harvested separately and virus titers were quantified by plaque assay. Variations of this screening protocol determined the effects of a number of shortened S. nigra extract treatments. Finally, S. nigra extract-treated virions were visualized by transmission electron microscopy with negative staining.Virus titers from infected cells treated with R. rosea and N. sativa extracts were not substantially different from infected cells treated with solvent alone. However, treatment with S. nigra extracts reduced virus titers by four orders of magnitude at a multiplicity of infection (MOI) of 1 in a dose-responsive manner. Infection at a low MOI reduced viral titers by six orders of magnitude and pretreatment of virus was necessary, but not sufficient, for full virus inhibition. Electron microscopy of virions treated with S. nigra extract showed compromised envelopes and the presence of membrane vesicles, which suggested a mechanism of action. CONCLUSIONS: These results demonstrate that S. nigra extract can inhibit IBV at an early point in infection, probably by rendering the virus non-infectious. They also suggest that future studies using S. nigra extract to treat or prevent IBV or other coronaviruses are warranted.

Differential regulation of two palmitoylation sites in the cytoplasmic tail of the beta1-adrenergic receptor.

S-Palmitoylation of G protein-coupled receptors (GPCRs) is a prevalent modification, contributing to the regulation of receptor function. Despite its importance, the palmitoylation status of the ß(1)-adrenergic receptor, a GPCR critical for heart function, has never been determined. We report here that the ß(1)-adrenergic receptor is palmitoylated on three cysteine residues at two sites in the C-terminal tail. One site (proximal) is adjacent to the seventh transmembrane domain and is a consensus site for GPCRs, and the other (distal) is downstream. These sites are modified in different cellular compartments, and the distal palmitoylation site contributes to efficient internalization of the receptor following agonist stimulation. Using a bioorthogonal palmitate reporter to quantify palmitoylation accurately, we found that the rates of palmitate turnover at each site are dramatically different. Although palmitoylation at the proximal site is remarkably stable, palmitoylation at the distal site is rapidly turned over. This is the first report documenting differential dynamics of palmitoylation sites in a GPCR. Our results have important implications for function and regulation of the clinically important ß(1)-adrenergic receptor.