Radiological Progression of Degenerative Cervical Myelopathy in a Clinically Stable Patient: Case Report.

Degenerative cervical myelopathy (DCM) is a common neurological condition, with disease progression that is both variable and difficult to predict. Here, we present a case of DCM in a gentleman in his late 60s with significant radiological disease progression without consequent change in clinical symptoms. The case serves as a reminder of an enduring medical aphorism that clinical history and examination should be prioritized above more complex data, such as imaging investigations. In addition, the case also highlights that guidelines should be contextualized within individual clinical circumstances.

Naturally sterile Mus spretus hybrids are suitable for the generation of pseudopregnant embryo transfer recipients.

For the preparation of embryo transfer recipients, surgically vasectomized mice are commonly used, generated by procedures associated with pain and discomfort. Sterile transgenic strains provide a nonsurgical replacement, but their maintenance requires breeding and genotyping procedures. We have previously reported the use of naturally sterile STUSB6F1 hybrids for the production of embryo transfer recipients and found the behavior of these recipients to be indistinguishable from those generated by vasectomized males. The method provides two substantial 3R impacts: refinement (when compared with surgical vasectomy) and reduction in breeding procedures (compared with sterile transgenic lines). Despite initial promise, the 3Rs impact of this innovation was limited by difficulties in breeding the parental STUS/Fore strain, which precluded the wider distribution of the sterile hybrid. The value of a 3R initiative is only as good as the uptake in the community. Here we, thus, select a different naturally sterile hybrid, generated from strains that are widely available: the B6SPRTF1 hybrid between C57BL/6J and Mus spretus. We first confirmed its sterility by sperm counting and testes weight and then trialed the recovery of cryopreserved embryos and germplasm within three UK facilities. Distribution of sperm for the generation of these hybrids by in vitro fertilization was found to be the most robust distribution method and avoided the need to maintain a live M. spretus colony. We then tested the suitability of B6SPRTF1 sterile hybrids for the generation of embryo transfer recipients at these same three UK facilities and found the hybrids to be suitable when compared with surgical vasectomized mice and a sterile transgenic strain. In conclusion, the potential 3Rs impact of this method was confirmed by the ease of distribution and the utility of sterile B6SPRTF1 hybrids at independent production facilities.

Finite Element Analysis for Degenerative Cervical Myelopathy: Scoping Review of the Current Findings and Design Approaches, Including Recommendations on the Choice of Material Properties.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a slow-motion spinal cord injury caused via chronic mechanical loading by spinal degenerative changes. A range of different degenerative changes can occur. Finite element analysis (FEA) can predict the distribution of mechanical stress and strain on the spinal cord to help understand the implications of any mechanical loading. One of the critical assumptions for FEA is the behavior of each anatomical element under loading (ie, its material properties). OBJECTIVE: This scoping review aims to undertake a structured process to select the most appropriate material properties for use in DCM FEA. In doing so, it also provides an overview of existing modeling approaches in spinal cord disease and clinical insights into DCM. METHODS: We conducted a scoping review using qualitative synthesis. Observational studies that discussed the use of FEA models involving the spinal cord in either health or disease (including DCM) were eligible for inclusion in the review. We followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The MEDLINE and Embase databases were searched to September 1, 2021. This was supplemented with citation searching to retrieve the literature used to define material properties. Duplicate title and abstract screening and data extraction were performed. The quality of evidence was appraised using the quality assessment tool we developed, adapted from the Newcastle-Ottawa Scale, and shortlisted with respect to DCM material properties, with a final recommendation provided. A qualitative synthesis of the literature is presented according to the Synthesis Without Meta-Analysis reporting guidelines. RESULTS: A total of 60 papers were included: 41 (68%) "FEA articles" and 19 (32%) "source articles." Most FEA articles (33/41, 80%) modeled the gray matter and white matter separately, with models typically based on tabulated data or, less frequently, a hyperelastic Ogden variant or linear elastic function. Of the 19 source articles, 14 (74%) were identified as describing the material properties of the spinal cord, of which 3 (21%) were considered most relevant to DCM. Of the 41 FEA articles, 15 (37%) focused on DCM, of which 9 (60%) focused on ossification of the posterior longitudinal ligament. Our aggregated results of DCM FEA indicate that spinal cord loading is influenced by the pattern of degenerative changes, with decompression alone (eg, laminectomy) sufficient to address this as opposed to decompression combined with other procedures (eg, laminectomy and fusion). CONCLUSIONS: FEA is a promising technique for exploring the pathobiology of DCM and informing clinical care. This review describes a structured approach to help future investigators deploy FEA for DCM. However, there are limitations to these recommendations and wider uncertainties. It is likely that these will need to be overcome to support the clinical translation of FEA to DCM.

Overarching Priorities for Health and Care Research in the United Kingdom: A Coproduced Synthesis of James Lind Alliance 'Top 10s'.

INTRODUCTION: James Lind Alliance (JLA) Priority Setting Partnerships (PSPs) produce 'Top 10' lists of health and care research priorities through a structured, shared decision-making process with patients or service users, carers and health or care professionals who identify questions that are most important to them. To date, over 150 PSPs in different areas of health and care have published research priorities. Some PSPs share similar priorities, which could be combined, promoted and addressed through collaborative research to increase value and reduce research waste. AIM: The aim of this study was to identify overarching themes common to JLA PSP priorities across different areas of health and care. METHODS: Our analysis included 'Top 10' research priorities produced by UK-based JLA PSPs between 2016 and 2020. The priorities were coded deductively by the Health Research Classification System (HRCS) health category and research activity. We then carried out online workshops with patients, service users and carers to generate new codes not already captured by this framework. Within each code, multistakeholder inductive thematic analysis was used to identify overarching themes, defined as encompassing priorities from three or more PSPs covering two or more health categories. We used codesign methods to produce an interactive tool for end users to navigate the overarching themes. RESULTS: Five hundred and fifteen research priorities from 51 PSPs were included in our analysis. The priorities together encompassed 20 of 21 HRCS health categories, the most common being 'generic health relevance' (22%), 'mental health' (18%) and 'musculoskeletal' (14%). We identified 89 overarching themes and subthemes, which we organised into a hierarchy with seven top-level themes: quality of life, caregivers and families, causes and prevention, screening and diagnosis, treatment and management, services and systems and social influences and impacts. CONCLUSION: There are many overarching themes common to research priorities across multiple areas of health and care. To facilitate new research and research funding, we have developed an interactive tool to help researchers, funders and patients or service users to explore these priority topics. This is freely available to download online. PATIENT OR PUBLIC CONTRIBUTION: Patients or service users and carers were involved throughout the study, including deciding the aims, designing the study, analysing priorities to identify themes, interpreting and reporting the findings.

Reliability of a Smartphone App to Objectively Monitor Performance Outcomes in Degenerative Cervical Myelopathy: Observational Study.

BACKGROUND: Developing new clinical measures for degenerative cervical myelopathy (DCM) is an AO Spine RECODE-DCM Research, an international and multi-stakeholder partnership, priority. Difficulties in detecting DCM and its changes cause diagnostic and treatment delays in clinical settings and heightened costs in clinical trials due to elevated recruitment targets. Digital outcome measures can tackle these challenges due to their ability to measure disease remotely, repeatedly, and more economically. OBJECTIVE: The aim of this study is to assess the reliability of the MoveMed battery of performance outcome measures. METHODS: A prospective observational study in decentralized secondary care was performed in England, United Kingdom. The primary outcome was to determine the test-retest reliability of the MoveMed performance outcomes using the intraclass correlation (ICC) of agreement . The secondary outcome was to determine the measurement error of the MoveMed performance outcomes using both the SE of the mean (SEM) of agreement and the smallest detectable change (SDC) of agreement . Criteria from the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) manual were used to determine adequate reliability (ie, ICC of agreement ≥0.7) and risk of bias. Disease stability was controlled using 2 minimum clinically important difference (MCID) thresholds obtained from the literature on the patient-derived modified Japanese Orthopaedic Association (p-mJOA) score, namely, MCID ≤1 point and MCID ≤2 points. RESULTS: In total, 7 adults aged 59.5 (SD 12.4) years who live with DCM and possess an approved smartphone participated in the study. All tests demonstrated moderate to excellent test-retest coefficients and low measurement errors. In the MCID ≤1 group, ICC of agreement values were 0.84-0.94 in the fast tap test, 0.89-0.95 in the hold test, 0.95 in the typing test, and 0.98 in the stand and walk test. SEM of agreement values were ±1 tap, ±1%-3% stability score points, ±0.06 keys per second, and ±10 steps per minute, respectively. SDC of agreement values were ±3 taps, ±4%-7% stability score points, ±0.2 keys per second, and ±27 steps per minute, respectively. In the MCID ≤2 group, ICC of agreement values were 0.61-0.91, 0.75-0.77, 0.98, and 0.62, respectively; SEM of agreement values were ±1 tap, ±2%-4% stability score points, ±0.06 keys per second, and ±10 steps per minute, respectively; and SDC of agreement values were ±3-7 taps, ±7%-10% stability score points, ±0.2 keys per second, and ±27 steps per minute, respectively. Furthermore, the fast tap, hold, and typing tests obtained sufficient ratings (ICC of agreement ≥0.7) in both MCID ≤1 and MCID ≤2 groups. No risk of bias factors from the COSMIN Risk of Bias checklist were recorded. CONCLUSIONS: The criteria from COSMIN provide "very good" quality evidence of the reliability of the MoveMed tests in an adult population living with DCM.

In the Murine and Bovine Maternal Mammary Gland Signal Transducer and Activator of Transcription 3 is Activated in Clusters of Epithelial Cells around the Day of Birth.

Signal transducers and activators of transcription (STAT) proteins regulate mammary development. Here we investigate the expression of phosphorylated STAT3 (pSTAT3) in the mouse and cow around the day of birth. We present localised colocation analysis, applicable to other mammary studies requiring identification of spatially congregated events. We demonstrate that pSTAT3-positive events are multifocally clustered in a non-random and statistically significant fashion. Arginase-1 expressing cells, consistent with macrophages, exhibit distinct clustering within the periparturient mammary gland. These findings represent a new facet of mammary STAT3 biology, and point to the presence of mammary sub-microenvironments.

Frequent disturbances enhanced the resilience of past human populations.

The record of past human adaptations provides crucial lessons for guiding responses to crises in the future1-3. To date, there have been no systematic global comparisons of humans' ability to absorb and recover from disturbances through time4,5. Here we synthesized resilience across a broad sample of prehistoric population time-frequency data, spanning 30,000 years of human history. Cross-sectional and longitudinal analyses of population decline show that frequent disturbances enhance a population's capacity to resist and recover from later downturns. Land-use patterns are important mediators of the strength of this positive association: farming and herding societies are more vulnerable but also more resilient overall. The results show that important trade-offs exist when adopting new or alternative land-use strategies.

Cost-effectiveness of surgery for degenerative cervical myelopathy in the United Kingdom.

PURPOSE: Degenerative cervical myelopathy (DCM) is the commonest cause of adult spinal cord dysfunction worldwide, for which surgery is the mainstay of treatment. At present, there is limited literature on the costs associated with the surgical management of DCM, and none from the United Kingdom (UK). This study aimed to evaluate the cost-effectiveness of DCM surgery within the National Health Service, UK. MATERIALS AND METHODS: Incidence of DCM was identified from the Hospital Episode Statistics (HES) database for a single year using five ICD-10 diagnostic codes to represent DCM. Health Resource Group (HRG) data was used to estimate the mean incremental surgery (treatment) costs compared to non-surgical care, and the incremental effect (quality adjusted life year (QALY) gain) was based on data from a previous study. A cost per QALY value of <£30,000/QALY (GBP) was considered acceptable and cost-effective, as per the National Institute for Health and Clinical Excellence (NICE) guidance. A sensitivity analysis was undertaken (±5%, ±10% and ±20%) to account for variance in both the cost of admission and QALY gain. RESULTS: The total number of admissions for DCM in 2018 was 4,218. Mean age was 62 years, with 54% of admissions being of working age (18-65 years). The overall estimated cost of admissions for DCM was £38,871,534 for the year. The mean incremental (per patient) cost of surgical management of DCM was estimated to be £9,216 (ranged £2,358 to £9,304), with a QALY gain of 0.64, giving an estimated cost per QALY value of £14,399/QALY. Varying the QALY gain by ±20%, resulted in cost/QALY figures between £12,000 (+20%) and £17,999 (-20%). CONCLUSIONS: Surgery is estimated to be a cost-effective treatment of DCM amongst the UK population.

Variation of practice in the treatment of pyogenic spondylodiscitis: a European Association of Neurosurgical Societies Spine Section study.

OBJECTIVE: The incidence of spondylodiscitis is rising across Europe, but the ideal treatment approach remains controversial. The choice between conservative and surgical therapies is ambiguous due to a lack of consensus. This European survey aimed to explore prevailing treatment paradigms for primary spondylodiscitis. METHODS: Spine neurosurgeons were invited through the European Association of Neurosurgical Societies Spine Section's mailing list to participate in an online survey featuring 7 spondylodiscitis case vignettes. Along with general management queries, specific patient treatment questions were posed. Data analysis was performed using R software (version 4.0.4). The index of qualitative variation (IQV) was calculated to quantify the variability in responses. RESULTS: A total of 130 responses were collected, comprising 86.9% board-certified neurosurgeons and 13.1% neurosurgeons in training, with an average of 11 years of practice. Most respondents performed 50-100 spine surgeries annually, with 66.7% specializing in spine surgery. An epidural empyema causing pronounced neurological deficits influenced 95.4% toward a surgical intervention, and mild neurological deficits and challenges in pathogen identification prompted 72.3% and 80%, respectively, to consider a surgical approach. Vertebral body destruction and spinal deformity directed 60% and 66.2%, respectively, toward surgery, whereas advanced age and comorbidities had a much smaller impact-5.4% and 9.2%, respectively. Clinical vignettes highlighted a predominant preference for conservative treatment in specific cases, with statistical significance (p < 0.05). The IQV values evaluated for each question ranged from 0.88 to 0.99, indicating low agreement across all questions among respondents. When examining the average IQV by country, intercountry variations in IQV were substantial, as illustrated by the diverse range of overall mean IQV values (0.15-0.85). CONCLUSIONS: The findings reveal a significant variability in the treatment of spondylodiscitis among European neurosurgeons, with most neurosurgeons opting for conservative treatment. These diverse strategies, both between and within countries, highlight an imperative for evidence-backed guidelines and consensus statements for this grave condition.

Mapping the Degenerative Cervical Myelopathy Research Landscape: Topic Modeling of the Literature.

STUDY DESIGN: Topic modeling of literature. OBJECTIVES: Our study has 2 goals: (i) to clarify key themes in degenerative cervical myelopathy (DCM) research, and (ii) to evaluate the current trends in the popularity or decline of these topics. Additionally, we aim to highlight the potential of natural language processing (NLP) in facilitating research syntheses. METHODS: Documents were retrieved from Scopus, preprocessed, and modeled using BERTopic, an NLP-based topic modeling method. We specified a minimum topic size of 25 documents and 50 words per topic. After the models were trained, they generated a list of topics and corresponding representative documents. We utilized linear regression models to examine trends within the identified topics. In this context, topics exhibiting increasing linear slopes were categorized as "hot topics," while those with decreasing slopes were categorized as "cold topics". RESULTS: Our analysis retrieved 3510 documents that were classified into 21 different topics. The 3 most frequently occurring topics were "OPLL" (ossification of the posterior longitudinal ligament), "Anterior Fusion," and "Surgical Outcomes." Trend analysis revealed the hottest topics of the decade to be "Animal Models," "DCM in the Elderly," and "Posterior Decompression" while "Morphometric Analyses," "Questionnaires," and "MEP and SSEP" were identified as being the coldest topics. CONCLUSIONS: Our NLP methodology conducted a thorough and detailed analysis of DCM research, uncovering valuable insights into research trends that were otherwise difficult to discern using traditional techniques. The results provide valuable guidance for future research directions, policy considerations, and identification of emerging trends.

An ovine model for investigation of the microenvironment of the male mammary gland.

The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland persists postnatally. We suggest that the male ovine mammary gland constitutes a promising adjunctive model for the male breast. In this study, we evaluate the male ovine mammary gland microenvironment, comparing intact and neutered males. Assessment of the glandular histo-anatomy highlights the resemblance of the male gland to that of neonatal female sheep and confirms the presence of rudimentary terminal duct lobular units. Irrespective of neutered status, cell proliferation in epithelial and stromal compartments is similarly low in males, and cell proliferation in epithelial cells and in the intralobular stroma is significantly lower than in pubertal female sheep. Between 42% and 72% of the luminal mammary epithelial cells in the male gland express the androgen receptor and expression is significantly reduced by neutering. Luminal epithelial cells within the intact and neutered male gland also express oestrogen receptor alpha, but minimal progesterone receptor expression is observed. The distribution of leukocytes within the ducts and stroma is similar to the mammary gland of female sheep and females of other species. Both macrophages and T lymphocytes are intercalated in the epithelial bilayer and are more abundant in the intralobular stroma than the interlobular stroma, suggesting that they may have a protective immunological function within the vestigial glandular tissue of the male sheep. Mast cells are also observed within the stroma. These cells cluster near the glandular tissue and are frequently located adjacent to blood vessels. The abundance of mast cells is significantly higher in intact males compared to neutered males, suggesting that hormone signalling may impact mast cell recruitment. In this study, we demonstrate the utility of the male ovine mammary gland as a model for furthering our knowledge of postnatal male mammary biology.

Increasing Knockin Efficiency in Mouse Zygotes by Transient Hypothermia.

Integration of a point mutation to correct or edit a gene requires the repair of the CRISPR-Cas9-induced double-strand break by homology-directed repair (HDR). This repair pathway is more active in late S and G2 phases of the cell cycle, whereas the competing pathway of nonhomologous end-joining (NHEJ) operates throughout the cell cycle. Accordingly, modulation of the cell cycle by chemical perturbation or simply by the timing of gene editing to shift the editing toward the S/G2 phase has been shown to increase HDR rates. Using a traffic light reporter in mouse embryonic stem cells and a fluorescence conversion reporter in human-induced pluripotent stem cells, we confirm that a transient cold shock leads to an increase in the rate of HDR, with a corresponding decrease in the rate of NHEJ repair. We then investigated whether a similar cold shock could lead to an increase in the rate of HDR in the mouse embryo. By analyzing the efficiency of gene editing using single nucleotide polymorphism changes and loxP insertion at three different genetic loci, we found that a transient reduction in temperature after zygote electroporation of CRISPR-Cas9 ribonucleoprotein with a single-stranded oligodeoxynucleotide repair template did indeed increase knockin efficiency, without affecting embryonic development. The efficiency of gene editing with and without the cold shock was first assessed by genotyping blastocysts. As a proof of concept, we then confirmed that the modified embryo culture conditions were compatible with live births by targeting the coat color gene tyrosinase and observing the repair of the albino mutation. Taken together, our data suggest that a transient cold shock could offer a simple and robust way to improve knockin outcomes in both stem cells and zygotes.

Challenges and patient outcomes in chronic subdural haematoma at the level of a regional care system A multi-centre, mixed-methods study from the East of England.

BACKGROUND: Chronic subdural haematoma (cSDH) is a common neurosurgical pathology affecting older patients with other health conditions. A significant proportion (up-to 90%) of referrals for surgery in neurosciences units (NSU) come from secondary care. However, the organisation of this care and the experience of patients repatriated to non-specialist centres are currently unclear. OBJECTIVES: This study aimed to clarify patient outcome in non-specialist centres following NSU discharge for cSDH surgery and to understand key system challenges. The study was set within a representative neurosurgical care system in the east of England. DESIGN AND METHODS: We performed a retrospective cohort analysis of patients referred for cSDH surgery. Alongside case record review, patient and staff experience were explored using surveys as well as an interactive c-design workshop. Challenges were identified from thematic analysis of survey responses and triangulated by focussed workshop discussions. RESULTS: Data on 381 patients referred for cSDH surgery from six centres was reviewed. One hundred and fifty-six (41%) patients were repatriated following surgery. Sixty-one (39%) of those repatriated suffered an inpatient complication (new infection, troponin rise or renal injury) following NSU discharge, with 58 requiring institutional discharge or new care. Surveys for staff (n = 42) and patients (n = 209) identified that resourcing, communication, and inter-hospital distance posed care challenges. This was corroborated through workshop discussions with stakeholders from two institutions. CONCLUSIONS: A significant amount of perioperative care for cSDH is delivered outside of specialist centres. Future improvement initiatives must recognise the system-wide nature of delivery and the challenges such an arrangement presents.

Impact of antithrombotic agents on outcomes in patients requiring surgery for chronic subdural haematoma: a systematic review and meta-analysis.

A chronic subdural haematoma (CSDH) is a collection of aged blood between the dura and the brain, typically treated with surgical evacuation. Many patients with CSDH have comorbidities requiring the use of antithrombotic medications. The optimal management of these medications in the context of CSDH remains unknown, as the risk of recurrence must be carefully weighed against the risk of vaso-occlusive events. To better understand these risks and inform the development of clinical practice guidelines, we conducted a systematic review and meta-analysis. A systematic review was conducted in accordance with the PRISMA guidelines, searching Medline and Embase databases. The study was registered with PROSPERO (CRD42023397061). A total of 44 studies were included, encompassing 1 prospective cohort study and 43 retrospective cohort studies. Pooled odds ratios (ORs) were calculated for CSDH recurrence and vaso-occlusive events in patients taking anticoagulant or antiplatelet medications compared to patients not receiving antithrombotic therapy. GRADE was used to assess the quality of evidence. In patients on anticoagulant therapy at CSDH diagnosis, the pooled OR for CSDH recurrence was 1.41 (95% CI 1.11 to 1.79; I2 = 28%). For patients on antiplatelet therapy, the pooled OR was 1.31 (95% CI 1.08 to 1.58; I2 = 32%). Patients taking antithrombotic medications had a significantly higher risk of vaso-occlusive events, with a pooled OR of 3.74 (95% CI 2.12 to 6.60; I2 = 0%). There was insufficient evidence to assess the impact of time to recommence antithrombotic medication on CSDH outcomes. We found that baseline antithrombotic use is associated with the risk of CSDH recurrence and vaso-occlusive events following surgical evacuation. The evidence base is of low quality, and decisions regarding antithrombotic therapy should be individualised for each patient. Further high-quality, prospective studies or registry-based designs are needed to better inform clinical decision-making and establish evidence-based guidelines.

Predictors of persistent opioid use in bladder cancer patients undergoing radical cystectomy: A SEER-Medicare analysis.

PURPOSE: To evaluate patient and provider characteristics that predict persistent opioid use following radical cystectomy for bladder cancer including non-opioid naïve patients. METHODS: Patients undergoing cystectomy between July 2007 and December 2015 were identified using the SEER-Medicare database. Opioid exposure was identified before and after cystectomy using Medicare Part D data. Multivariable analyses were used to identify predictors of the primary outcomes: persistent opioid use (prescription 3-6 months after surgery) and postoperative opioid prescriptions (within 30 days of surgery). Secondary outcomes included physician prescribing practices and rates of persistent opioid use in their patient cohorts. RESULTS: A total of 1,774 patients were included; 29% had prior opioid exposure. Compared to opioid-naïve patients, non-opioid naïve patients were more frequently younger, Black, and living in less educated communities. The percentage of persistent postoperative use was 10% overall and 24% in non-opioid naïve patients. Adjusting for patient factors, opioid naïve individuals were less likely to develop persistent use (OR 0.23) while a 50-unit increase in oral morphine equivalent per day prescribed following surgery nearly doubled the likelihood of persistent use (OR 1.98). Practice factors such as hospital size, teaching affiliation, and hospital ownership failed to predict persistent use. 29% of patients filled an opioid prescription postoperatively. Opioid naïve patients (OR 0.13) and those cared for at government hospitals (OR 0.59) were less likely to fill an opioid script along with those residing in the Northeast. Variability between physicians was seen in prescribing practices and rates of persistent use. CONCLUSIONS: Non-opioid naïve patients have higher rates of post-operative opioid prescription than opioid-naïve patients. Physician prescribing practices play a role in persistent use, as initial prescription amount predicts persistent use even in non-opioid naïve patients. Significant physician variation in both prescribing practices and rates of persistent use suggest a role for standardizing practices.

Scoping Review with Topic Modeling on the Diagnostic Criteria for Degenerative Cervical Myelopathy.

STUDY DESIGN: This study is a scoping review. OBJECTIVE: There is a broad variability in the definition of degenerative cervical myelopathy (DCM) and no standardized set of diagnostic criteria to date. METHODS: We interrogated the Myelopathy.org database, a hand-indexed database of primary clinical studies conducted exclusively on DCM in humans between 2005-2021. The DCM inclusion criteria used in these studies were inputted into 3 topic modeling algorithms: Hierarchical Dirichlet Process (HDP), Latent Dirichlet Allocation (LDA), and BERtopic. The emerging topics were subjected to manual labeling and interpretation. RESULTS: Of 1676 reports, 120 papers (7.16%) had well-defined inclusion criteria and were subjected to topic modeling. Four topics emerged from the HDP model: disturbance from extremity weakness and motor signs; fine-motor and sensory disturbance of upper extremity; a combination of imaging and clinical findings is required for the diagnosis; and "reinforcing" (or modifying) factors that can aid in the diagnosis in borderline cases. The LDA model showed the following topics: disturbance to the patient is required for the diagnosis; reinforcing factors can aid in the diagnosis in borderline cases; clinical findings from the extremities; and a combination of imaging and clinical findings is required for the diagnosis. BERTopic identified the following topics: imaging abnormality, typical clinical features, range of objective criteria, and presence of clinical findings. CONCLUSIONS: This review provides quantifiable data that only a minority of past studies in DCM provided meaningful inclusion criteria. The items and patterns found here are very useful for the development of diagnostic criteria for DCM.

Interventions to Optimize Spinal Cord Perfusion in Patients With Acute Traumatic Spinal Cord Injury: An Updated Systematic Review.

STUDY DESIGN: Systematic review update. OBJECTIVES: Interventions that aim to optimize spinal cord perfusion are thought to play an important role in minimizing secondary ischemic damage and improving outcomes in patients with acute traumatic spinal cord injuries (SCIs). However, exactly how to optimize spinal cord perfusion and enhance neurologic recovery remains controversial. We performed an update of a recent systematic review (Evaniew et al, J. Neurotrauma 2020) to evaluate the effects of Mean Arterial Pressure (MAP) support or Spinal Cord Perfusion Pressure (SCPP) support on neurological recovery and rates of adverse events among patients with acute traumatic SCI. METHODS: We searched PubMed/MEDLINE, EMBASE and ClinicalTrials.gov for new published reports. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. We implemented the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to rate confidence in the quality of the evidence. RESULTS: From 569 potentially relevant new citations since 2019, we identified 9 new studies for inclusion, which were combined with 19 studies from a prior review to give a total of 28 studies. According to low or very low quality evidence, the effect of MAP support on neurological recovery is uncertain, and increased SCPP may be associated with improved neurological recovery. Both approaches may involve risks for specific adverse events, but the importance of these adverse events to patients remains unclear. Very low quality evidence failed to yield reliable guidance about particular monitoring techniques, perfusion ranges, pharmacological agents, or durations of treatment. CONCLUSIONS: This update provides an evidence base to support the development of a new clinical practice guideline for the hemodynamic management of patients with acute traumatic SCI. While avoidance of hypotension and maintenance of spinal cord perfusion are important principles in the management of an acute SCI, the literature does not provide high quality evidence in support of a particular protocol. Further prospective, controlled research studies with objective validated outcome assessments are required to examine interventions to optimize spinal cord perfusion in this setting.

Timing of Decompressive Surgery in Patients With Acute Spinal Cord Injury: Systematic Review Update.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Surgical decompression is a cornerstone in the management of patients with traumatic spinal cord injury (SCI); however, the influence of the timing of surgery on neurological recovery after acute SCI remains controversial. This systematic review aims to summarize current evidence on the effectiveness, safety, and cost-effectiveness of early (≤24 hours) or late (>24 hours) surgery in patients with acute traumatic SCI for all levels of the spine. Furthermore, this systematic review aims to evaluate the evidence with respect to the impact of ultra-early surgery (earlier than 24 hours from injury) on these outcomes. METHODS: A systematic search of the literature was performed using the MEDLINE database (PubMed), Cochrane database, and EMBASE. Two reviewers independently screened the citations from the search to determine whether an article satisfied predefined inclusion and exclusion criteria. For all key questions, we focused on primary studies with the least potential for bias and those that controlled for baseline neurological status and specified time from injury to surgery. Risk of bias of each article was assessed using standardized tools based on study design. Finally, the overall strength of evidence for the primary outcomes was assessed using the GRADE approach. Data were synthesized both qualitatively and quantitively using meta-analyses. RESULTS: Twenty-one studies met inclusion and exclusion criteria and formed the evidence base for this review update. Seventeen studies compared outcomes between patients treated with early (≤24 hours from injury) compared to late (>24 hours) surgical decompression. An additional 4 studies evaluated even earlier time frames: <4, <5, <8 or <12 hours. Based on moderate evidence, patients were 2 times more likely to recover by ≥ 2 grades on the ASIA Impairment Score (AIS) at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, moderate evidence suggested that patients receiving early decompression had an additional 4.50 (95% CI 1.70 to 7.29) point improvement on the ASIA motor score. With respect to administrative outcomes, there was low evidence that early decompression may decrease acute hospital length of stay. In terms of safety, there was moderate evidence that suggested the rate of major complications does not differ between patients undergoing early compared to late surgery. Furthermore, there was no difference in rates of mortality, surgical device-related complications, sepsis/systemic infection or neurological deterioration based on timing of surgery. Firm conclusions were not possible with respect to the impact of ultra-early surgery on neurological, functional or safety outcomes given the poor-quality studies, imprecision and the overlap in the time frames examined. CONCLUSIONS: This review provides an evidence base to support the update on clinical practice guidelines related to the timing of surgical decompression in acute SCI. Overall, the strength of evidence was moderate that early surgery (≤24 hours from injury) compared to late (>24 hours) results in clinically meaningful improvements in neurological recovery. Further studies are required to delineate the role of ultra-early surgery in patients with acute SCI.

Donor template delivery by recombinant adeno-associated virus for the production of knock-in mice.

BACKGROUND: The ability of recombinant adeno-associated virus to transduce preimplantation mouse embryos has led to the use of this delivery method for the production of genetically altered knock-in mice via CRISPR-Cas9. The potential exists for this method to simplify the production and extend the types of alleles that can be generated directly in the zygote, obviating the need for manipulations of the mouse genome via the embryonic stem cell route. RESULTS: We present the production data from a total of 13 genetically altered knock-in mouse models generated using CRISPR-Cas9 electroporation of zygotes and delivery of donor repair templates via transduction with recombinant adeno-associated virus. We explore the efficiency of gene targeting at a total of 12 independent genetic loci and explore the effects of allele complexity and introduce strategies for efficient identification of founder animals. In addition, we investigate the reliability of germline transmission of the engineered allele from founder mice generated using this methodology. By comparing our production data against genetically altered knock-in mice generated via gene targeting in embryonic stem cells and their microinjection into blastocysts, we assess the animal cost of the two methods. CONCLUSIONS: Our results confirm that recombinant adeno-associated virus transduction of zygotes provides a robust and effective delivery route for donor templates for the production of knock-in mice, across a range of insertion sizes (0.9-4.7 kb). We find that the animal cost of this method is considerably less than generating knock-in models via embryonic stem cells and thus constitutes a considerable 3Rs reduction.