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Background Spinal manipulative therapy (SMT) is a guideline-recommended treatment option for spinal pain. The recommendation is based on multiple systematic reviews. However, these reviews fail to consider that clinical effects may depend on SMT “application procedures” (i.e., how and where SMT is applied). Using network meta-analyses, we aim to investigate which SMT “application procedures” have the greatest magnitude of clinical effectiveness for reducing pain and disability, for any spinal complaint, at short-term and long-term follow-up. We will compare application procedural parameters by classifying the thrust application technique and the application site (patient positioning, assisted, vertebral target, region target, Technique name, forces, and vectors, application site selection approach and rationale) against: 1. Waiting list/no treatment; 2. Sham interventions not resembling SMT (e.g., detuned ultrasound); 3. Sham interventions resembling SMT; 4. Other therapies not recommended in clinical practice guidelines; and 5. Other therapies recommended in clinical practice guidelines. Secondly, we will examine how contextual elements, including procedural fidelity (whether the SMT was delivered as planned) and clinical applicability (whether the SMT is similar to clinical practice) of the SMT. Methods We will include randomized controlled trials (RCT) found through three search strategies, (i) exploratory, (ii) systematic, and (iii) other known sources. We define SMT as a high-velocity low-amplitude thrust or grade V mobilization. Eligibility is any RCT assessing SMT against any other type of SMT, any other active or sham intervention, or no treatment control on adult patients with pain in any spinal region. The RCTs must report on continuous pain intensity and/or disability outcomes. Two authors will independently review title and abstract screening, full-text screening, and data extraction. Spinal manipulative therapy techniques will be classified according to the technique application and choice of application sites. We will conduct a network-meta analysis using a frequentist approach and multiple subgroup and sensitivity analyses. Discussion This will be the most extensive review of thrust SMT to date, and will allow us to estimate the importance of different SMT application procedures used in clinical practice and taught across educational settings. Thus, the results are applicable to clinical practice, educational settings, and research studies. PROSPERO registration: CRD42022375836.

Musculoskeletal (MSK) health impairments contribute substantially to the pain and disability burden in low- and middle-income countries (LMICs), yet health systems strengthening (HSS) responses are nascent in these settings. We aimed to explore the contemporary context, framed as challenges and opportunities, for improving population-level prevention and management of MSK health in LMICs using secondary qualitative data from a previous study exploring HSS priorities for MSK health globally and (2) to contextualize these findings through a primary analysis of health policies for integrated management of non-communicable diseases (NCDs) in select LMICs. Part 1: 12 transcripts of interviews with LMIC-based key informants (KIs) were inductively analysed. Part 2: systematic content analysis of health policies for integrated care of NCDs where KIs were resident (Argentina, Bangladesh, Brazil, Ethiopia, India, Kenya, Malaysia, Philippines and South Africa). A thematic framework of LMIC-relevant challenges and opportunities was empirically derived and organized around five meta-themes: (1) MSK health is a low priority; (2) social determinants adversely affect MSK health; (3) healthcare system issues de-prioritize MSK health; (4) economic constraints restrict system capacity to direct and mobilize resources to MSK health; and (5) build research capacity. Twelve policy documents were included, describing explicit foci on cardiovascular disease (100%), diabetes (100%), respiratory conditions (100%) and cancer (89%); none explicitly focused on MSK health. Policy strategies were coded into three categories: (1) general principles for people-centred NCD care, (2) service delivery and (3) system strengthening. Four policies described strategies to address MSK health in some way, mostly related to injury care. Priorities and opportunities for HSS for MSK health identified by KIs aligned with broader strategies targeting NCDs identified in the policies. MSK health is not currently prioritized in NCD health policies among selected LMICs. However, opportunities to address the MSK-attributed disability burden exist through integrating MSK-specific HSS initiatives with initiatives targeting NCDs generally and injury and trauma care.

Background Previous studies have found that lumbar spinal stenosis (LSS) often co-occurs with knee or hip OA and can impact treatment response. However, it is unclear what participant characteristics may be helpful in identifying individuals with these co-occurring conditions. The aim of this cross-sectional study was to explore characteristics associated with comorbid symptoms of lumbar spinal stenosis (LSS) in people with knee or hip osteoarthritis (OA) enrolled in a primary care education and exercise program. Methods Sociodemographic, clinical characteristics, health status measures, and a self-report questionnaire on the presence of LSS symptoms was collected at baseline from the Good Life with osteoArthritis in Denmark primary care program for knee and hip OA. Cross-sectional associations between characteristics and the presence of comorbid LSS symptoms were assessed separately in participants with primary complaint of knee and hip OA, using domain-specific logistic models and a logistic model including all characteristics. Results A total of 6,541 participants with a primary complaint of knee OA and 2,595 participants with a primary complaint of hip OA were included, of which 40% and 50% reported comorbid LSS symptoms, respectively. LSS symptoms were associated with similar characteristics in knee and hip OA. Sick leave was the only sociodemographic variable consistently associated with LSS symptoms. For clinical characteristics, back pain, longer symptom duration and bilateral or comorbid knee or hip symptoms were also consistently associated. Health status measures were not consistently related to LSS symptoms. Conclusion Comorbid LSS symptoms in people with knee or hip OA undergoing a primary care treatment program of group-based education and exercise were common and associated with a similar set of characteristics. These characteristics may help to identify people with co-occurring LSS and knee or hip OA, which can be used to help guide clinical decision-making.

Background Patient centred care is commonly recommended in clinical practice guidelines to improve patient outcomes and reduce healthcare costs. Identifying measurement tools used to assess healthcare students’ attitudes towards patient centered care and determining their attitudes is the first step to ensuring patient centred care is provided in the future. The primary aim of this review was to describe the measurement tools used to assess healthcare students’ attitudes towards patient centred care. The secondary aim was to quantify healthcare students’ attitudes towards patient centred care. Methods An electronic database search was conducted in MEDLINE, EMBASE, CINAHL from inception until March 1, 2021, with combined terms relating to ‘patient centred care’, ‘attitudes’, and ‘healthcare students’. Studies that quantitatively assessed healthcare students’ attitudes towards patient centred care were included. Measurement tools used in the included studies were qualitatively described. Meta-analysis was conducted to quantify healthcare students’ attitudes towards patient centred care and assess the respective influence of gender, profession, and study geographical location on healthcare students’ attitudes towards patient centred care. Results The electronic search identified 3948 total studies. One hundred twenty-nine full texts were screened, and 49 studies were included. There were 16 measurement tools used to assess healthcare students’ attitudes towards patient centered care. Most studies (53%, n = 26) used the Patient-Practitioner Orientation Scale (PPOS) to assess patient centered care. Meta-analyses of 20 studies with 26 total groups resulted in a pooled mean PPOS score of 4.16 on a 0–6 scale (95% Confidence Interval [CI]: 3.95, 4.37), indicating low attitudes towards patient centered care. Additional analyses found that women have significantly higher attitudes towards patients centred care than men (pooled effect 0.14 [95% CI: 0.05, 0.23], n = 8 studies) and mean PPOS scores appear similar among sub-groups of only medical students (pooled mean 4.13, 95% CI: 3.85, 4.42, n = 13 studies) and only American healthcare students (pooled mean 4.49, 95% CI: 4.35, 4.64, n = 5 studies). Conclusions Several different measurement tools have been used to assess healthcare students’ attitudes towards patient centred care, but the most commonly used is the PPOS. Our results indicate that healthcare students have low attitudes towards patient centred care. Future studies should evaluate if attitudes towards patient centred care can be improved during healthcare education.

Background: Global policy to guide action on musculoskeletal (MSK) health is in a nascent phase. Lagging behind other noncommunicable diseases there is currently little global policy to assist governments to develop national approaches to MSK health. Considering the importance of comparison and learning for global policy development, we aimed to perform a comparative analysis of national MSK policies to identify areas of innovation and draw common themes and principles that could guide MSK health policy. Methods: Multi-modal search strategy incorporating a systematic online search targeted at the 30 most populated nations ; a call to networked experts; a specified question in a related eDelphi questionnaire; and snowballing methods.. Extracted data were organised using an a priori framework adapted from the WHO Building Blocks and further inductive coding. Subsequently, texts were open coded and thematically analysed to derive specific sub-themes and principles underlying texts within each theme, serving as abstracted, transferrable concepts for future global policy. Results: The search yielded 165 documents with 41 retained after removal of duplicates and exclusions. Only three documents were comprehensive national strategies addressing MSK health. The most common conditions addressed in the documents were pain (noncancer), low back pain, occupational health, inflammatory conditions, and osteoarthritis. Across eight categories, we derived 47 sub-themes with transferable principles that could guide global policy for: service delivery; workforce; medicines and technologies; financing; data and information systems; leadership and governance; citizens, consumers and communities; and research and innovation. Conclusion: There are few examples of national strategic policy to address MSK health; however, many countries are moving towards this by documenting the burden of disease and developing policies for MSK services. This review found a breadth of principles that can add to this existing work and may be adopted to develop comprehensive system-wide MSK health approaches at national and global levels.

ObjectiveWe synthesised and assessed credibility (ie, trustworthiness) of thresholds that define meaningful scores for patient-reported outcome measures (PROMs) following interventions for anterior cruciate ligament (ACL) tear or traumatic meniscus injury.DesignSystematic review, narrative synthesis.Data sourcesWe searched five databases, handsearched references of included studies and tracked citations.EligibilityIncluded studies investigated: individuals with ACL tear or meniscus injury; mean age ResultsWe included 18 studies (15 ACL, 3 meniscus). Three different methods were used to calculate anchor-based MICs across 9 PROMs, PASS thresholds across 4 PROMs and treatment failure for 1 PROM. Credibility was rated ‘high’ for only one study—an MIC of 18 for the Knee injury and Osteoarthritis Outcome Score Quality-of-life (KOOS-QOL) subscale (using the MID Credibility Assessment Tool). Where multiple thresholds were calculated among ‘low’ credibility thresholds in ACL studies, MICs converged to within a 10-point range for KOOS-Symptoms (−1.2 to 5.4) and function in daily living (activities of daily living, ADL 0.5–8.1) subscales, and the International Knee Documentation Committee Subjective Knee Form (7.1–16.2). Other PROM thresholds differed up to 30 points. PASS thresholds converged to within a 10-point range in KOOS-ADL for ACL tears (92.3–100), and KOOS-Symptoms (73-78) and KOOS-QOL (53-57) in meniscus injuries.ConclusionMeaningful PROM thresholds were highly susceptible to study heterogeneity. While PROM thresholds can aid interpretability in research and clinical practice, they should be cautiously interpreted.

Elsberg syndrome is a rare cause of lumbosacral radiculitis with concomitant thoracic and lumbosacral myelitis that can be seen after an acute or reactivated viral infection. After the initial coronavirus surge in New York City, a 68-year-old man developed progressive lower extremity weakness and a defined sensory level at the lower abdomen. He had highly elevated SARS-CoV-2 IgG antibodies despite an absence of preceding COVID-19 symptoms. Serial electrodiagnostic testing revealed absent lower extremity late responses, with otherwise normal distal sensorimotor conductions. Electromyography revealed active neurogenic changes and reduced motor unit recruitment in the L3-L4 myotomes. Treatment with methylprednisolone and intravenous immunoglobulin was followed by minimal clinical improvement but re-emergence of the lower extremity late responses on electrodiagnostic testing. We report here, to the best of our knowledge, the first case of suspected COVID-19-associated Elsberg syndrome, which expands the spectrum of neuromuscular manifestations associated with SARS-CoV-2 infection and sheds light on ways to approach diagnostic and treatment options for these patients.

Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System.This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis.Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction90%). For the super responders, two of the four patients had the device implanted for2 years. The response rate was 70% for those in whom the device was implanted for2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported.Based on the authors' experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE.

Background Musculoskeletal multimorbidity is common and coexisting lumbar spinal stenosis (LSS) with knee or hip osteoarthritis (OA) has been reported. The aim of this review was to report the prevalence of multimorbid degenerative LSS with knee or hip OA based on clinical and/or imaging case definitions. Methods Literature searches were performed in MEDLINE, EMBASE, CENTRAL, and CINAHL up to May 2021. Studies involving adults with cross-sectional data to estimate the prevalence of co-occurring LSS with knee or hip OA were included. Study selection, data extraction, and risk of bias assessment were performed independently by two reviewers. Results were stratified according to index and comorbid condition, and by case definitions (imaging, clinical, and combined). Results Ten studies from five countries out of 3891 citations met the inclusion criteria. Sample sizes ranged from 44 to 2,857,999 (median 230) and the mean age in the included studies range from 61 to 73 years (median 66 years). All studies were from secondary care or mixed settings. Nine studies used a combined definition of LSS and one used a clinical definition. Imaging, clinical, and combined case definitions of knee and hip OA were used. The prevalence of multimorbid LSS and knee or hip OA ranged from 0 to 54%, depending on the specified index condition and case definitions used. Six studies each provided prevalence data for index LSS and comorbid knee OA (prevalence range: 5 to 41%) and comorbid hip OA (prevalence range: 2 to 35%). Two studies provided prevalence data for index knee OA and comorbid LSS (prevalence range 17 to 54%). No studies reporting prevalence data for index hip OA and comorbid LSS were found. Few studies used comparable case definitions and all but one study were rated as high risk of bias. Conclusions There is evidence that multimorbid LSS with knee or hip OA occurs in people (0 to 54%), although results are based on studies with high risk of bias and surgical populations. Variability in LSS and OA case definitions limit the comparability of studies and prevalence estimates should therefore be interpreted with caution. Review registration PROSPERO (CRD42020177759).

Objective: Globally 37.9 million people are living with HIV/AIDS, and with mortality rates declining, there is an increasing focus on comorbidities including musculoskeletal (MSK) disorders. Therefore, the aim of this scoping review was to generate and summarize an overview of the existing scientific literature dealing with MSK complaints in people living with HIV/AIDS (PLWHAs). Methods: This scoping review followed the five-stage methodological framework proposed by Arksey and O’Malley. We searched PubMed, EMBASE, CINAHL, and the Cochrane Library from inception to June 1, 2020. Two reviewers independently reviewed the articles for eligibility. A data extraction form was used to chart information such as author, year of publication, data source, sample size, country of origin, ethnicity, age, gender, antiretroviral therapy, MSK condition prevalence, and anatomical location. Results: The search identified 10 522 articles. Of these, 27 studies were included after full-text screening for data extraction. Studies were conducted in thirteen different countries with diverse data sources such as outpatient clinic files, hospital records, primary care clinic files, and AIDS Service Organization files. PLWHAs have a variety of MSK conditions. Most studies reported spinal pain such as lower back or neck pain, but pain in the extremities and osteoarthritis (OA) were also represented. However, the frequencies of pain at various anatomical sites were highly variable. Conclusion: There is a lack of knowledge regarding MSK conditions in PLWHAs. Future studies designed to specifically study MSK complaints and disabilities are needed to gain a better picture of the impact of these conditions in PLWHAs and to inform prevention and treatment strategies globally in this often-underserved population.

People with knee or hip osteoarthritis (OA) can experience comorbid lumbar spinal stenosis (LSS), but the impact on treatment outcomes is unknown. The aim of this study was to investigate associations between comorbid LSS symptoms and changes in pain, function, and quality of life following a patient education and exercise therapy program.This was a longitudinal analysis of 6813 participants in the Good Life with osteoArthritis in Denmark (GLA:D®) program; a structured patient education and exercise therapy program for knee and hip OA. Participants were classified as having comorbid LSS symptoms based on self-report symptom items. Linear mixed models were used to assess differences in change in pain, function, and quality of life outcomes (0 worst to 100 best) at 3- and 12-month follow-up.15% and 23% of knee and hip OA participants had comorbid LSS symptoms, respectively. Knee participants with comorbid LSS symptoms had smaller improvement in pain at 3-months (-1.7, 95% CI -3.3 to -0.1) and hip participants with comorbid LSS symptoms had greater improvement in function at 3- (2.5, 95% CI 0.5 to 5.0) and 12-months (3.8, 95% CI 0.9 to 6.6), when compared to those without LSS symptoms. These differences were not clinically significant and no differences in other outcomes were observed.Knee or hip OA patients with comorbid LSS symptoms should expect similar improvements in knee- or hip-related pain, function, and quality of life outcomes when undergoing a patient education and exercise therapy program compared to those without LSS symptoms.

To characterize continuous video electroencephalogram (VEEG) findings of hospitalized COVID-19 patients.We performed a retrospective chart review of patients admitted at three New York City hospitals who underwent VEEG at the peak of the COVID-19 pandemic. Demographics, comorbidities, neuroimaging, VEEG indications and findings, treatment, and outcomes were collected.Of 93 patients monitored, 77% had severe COVID-19 and 40% died. Acute ischemic or hemorrhagic stroke was present in 26% and 15%, respectively. Most common VEEG indications were encephalopathy/coma (60%) and seizure-like movements (38%). Most common VEEG findings were generalized slowing (97%), generalized attenuation (31%), generalized periodic discharges (17%) and generalized sharp waves (15%). Epileptiform abnormalities were present in 43% and seizures in 8% of patients, all of whom had seizure risk factors. Factors associated with an epileptiform VEEG included increasing age (OR 1.07, p = 0.001) and hepatic/renal failure (OR 2.99, p = 0.03).Most COVID-19 patients who underwent VEEG monitoring had severe COVID-19 and over one-third had acute cerebral injury (e.g., stroke, anoxia). Seizures were uncommon. VEEG findings were nonspecific.VEEG findings in this cohort of hospitalized COVID-19 patients were those often seen in critical illness. Seizures were uncommon and occurred in the setting of common seizure risk factors.

The essential role of membrane associated guanylate kinase 2 (MAGI2) in podocytes is indicated by the phenotypes of severe glomerulosclerosis of both MAGI2 knockout mice and in patients with congenital nephrotic syndrome (CNS) caused by mutations in MAGI2. Here, we show that MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor, RapGEF2, and that this complex is lost when expressing MAGI2 CNS variants. Co-expression of RapGEF2 with wild-type MAGI2, but not MAGI2 CNS variants, enhanced activation of the small GTPase Rap1, a central signaling node in podocytes. In mice, podocyte-specific RapGEF2 deletion resulted in spontaneous glomerulosclerosis, with qualitative glomerular features comparable to MAGI2 knockout mice. Knockdown of RapGEF2 or MAGI2 in human podocytes caused similar reductions in levels of Rap1 activation and Rap1-mediated downstream signaling. Furthermore, human podocytes expressing MAGI2 CNS variants show severe abnormalities of cellular morphology and dramatic loss of actin cytoskeletal organization, features completely rescued by pharmacological activation of Rap1 via a non-MAGI2 dependent upstream pathway. Finally, immunostaining of kidney sections from patients with congenital nephrotic syndrome and MAGI2 mutations showed reduced podocyte Rap1-mediated signaling. Thus, MAGI2-RapGEF2-Rap1 signaling is essential for normal podocyte function. Hence, disruption of this pathway is an important cause of the renal phenotype induced by MAGI2 CNS mutations.

Supplemental Digital Content is Available in the Text., Purpose: Patients undergoing epilepsy surgery often require invasive EEG, but few studies have examined the signal characteristics of contacts on the surface of the brain (electrocorticography, ECOG) versus depth contacts, used in stereoelectroencephalography (SEEG). As SEEG and ECOG have significant differences in complication rates, it is important to determine whether both modalities produce similar signals for analysis, to ultimately guide management of medically intractable epilepsy. Methods: Twenty-seven patients who underwent SEEG (19), ECOG (6), or both (2) were analyzed for quantitative measures of activity including spectral power and phase–amplitude coupling during approximately 1 hour of wakefulness. The position of the contacts was calculated by coregistering the postoperative computed tomography with a reconstructed preoperative MRI. Using two types of referencing schemes—local versus common average reference—the brain regions where any quantitative measure differed systematically with contact depth were established. Results: Using even the most permissive statistical criterion, few quantitative measures were significantly correlated with contact depth in either ECOG or SEEG contacts. The factors that predicted changes in spectral power and phase–amplitude coupling with contact depth were failing to baseline correct spectral power measures, use of a local rather than common average reference, using baseline correction for phase–amplitude coupling measures, and proximity of other grey matter structures near the region where the contact was located. Conclusions: The signals recorded by ECOG and SEEG have very similar spectral power and phase–amplitude coupling, suggesting that both modalities are comparable from an electrodiagnostic standpoint in delineation of the epileptogenic network.

Introduction: The management of musculoskeletal disorders is complex and requires a multidisciplinary approach. Manual therapies, such as spinal manipulative therapy (SMT), are often recommended as an adjunct treatment and appear to have demonstrable effects on pain and short-term disability in several spinal conditions. However, no definitive mechanism that can explain these effects has been identified. Identifying relevant prognostic factors is therefore recommended for people with back pain.Objective: The main purpose of this study was to identify short-term candidate prognostic factors for clinically significant responses in pain, disability and global perceived change (GPC) following a spinal manipulation treatment in patients with non-specific thoracic back pain.Methods: Patients seeking care for thoracic spine pain were invited to participate in the study. Pain levels were recorded at baseline, post-intervention, and 1 week after a single session of SMT. Disability levels were collected at baseline and at 1-week follow-up. GPC was collected post-intervention and at 1-week follow-up. Biomechanical parameters of SMT, expectations for improvement in pain and disability, kinesiophobia, anxiety levels as well as perceived comfort of spinal manipulative therapy were assessed.Analysis: Differences in baseline characteristics were compared between patients categorized as responders or non-responders based on their pain level, disability level, and GPC at each measurement time point. Binary logistic regression was calculated if the statistical significance level of group comparisons (responder vs. non-responders) was equal to, or Results: 107 patients (62 females and 45 males) were recruited. Mean peak force averaged 450.8 N with a mean thrust duration of 134.9 ms. Post-intervention, comfort was associated with pain responder status (p < 0.05) and GPC responder status (p < 0.05), while expectation of disability improvement was associated with GPC responder status (p < 0.05). At follow-up, comfort and expectation of pain improvement were associated with responder GPC status (p < 0.05). No association was found between responder pain, disability or GPC status and biomechanical parameters of SMT at any time point.Discussion: No specific dosage of SMT was associated with short-term clinical responses to treatment. However, expectations of improvement and patient comfort during SMT were associated with a positive response to treatment.

Background Musculoskeletal (MSK) conditions, MSK pain and MSK injury/trauma are the largest contributors to the global burden of disability, yet global guidance to arrest the rising disability burden is lacking. We aimed to explore contemporary context, challenges and opportunities at a global level and relevant to health systems strengthening for MSK health, as identified by international key informants (KIs) to inform a global MSK health strategic response. Methods An in-depth qualitative study was undertaken with international KIs, purposively sampled across high-income and low and middle-income countries (LMICs). KIs identified as representatives of peak global and international organisations (clinical/professional, advocacy, national government and the World Health Organization), thought leaders, and people with lived experience in advocacy roles. Verbatim transcripts of individual semi-structured interviews were analysed inductively using a grounded theory method. Data were organised into categories describing 1) contemporary context; 2) goals; 3) guiding principles; 4) accelerators for action; and 5) strategic priority areas (pillars), to build a data-driven logic model. Here, we report on categories 1–4 of the logic model. Results Thirty-one KIs from 20 countries (40% LMICs) affiliated with 25 organisations participated. Six themes described contemporary context (category 1): 1) MSK health is afforded relatively lower priority status compared with other health conditions and is poorly legitimised; 2) improving MSK health is more than just healthcare; 3) global guidance for country-level system strengthening is needed; 4) impact of COVID-19 on MSK health; 5) multiple inequities associated with MSK health; and 6) complexity in health service delivery for MSK health. Five guiding principles (category 3) focussed on adaptability; inclusiveness through co-design; prevention and reducing disability; a lifecourse approach; and equity and value-based care. Goals (category 2) and seven accelerators for action (category 4) were also derived. Conclusion KIs strongly supported the creation of an adaptable global strategy to catalyse and steward country-level health systems strengthening responses for MSK health. The data-driven logic model provides a blueprint for global agencies and countries to initiate appropriate whole-of-health system reforms to improve population-level prevention and management of MSK health. Contextual considerations about MSK health and accelerators for action should be considered in reform activities.

Knee and hip osteoarthritis (OA) place a significant burden on the Canadian health system and are a major public health challenge. This brief commentary discusses the recently published Osteoarthritis Research Society International guideline and the American College of Rheumatology guideline for the management of OA. Special attention has been given to the role of manual therapy, exercise, and patient education for the treatment of knee and hip OA. This article also reviews the Good Life with osteoArthritis in Denmark (GLA:DL’ostéoarthrite (OA) du genou et de la hanche impose un lourd fardeau économique au système de santé canadien et constitue un grave problème de santé publique. Le présent article porte sur la ligne directrice publiée récemment par l’Osteoarthritis Research Society International et la ligne directrice sur la prise en charge de l’ostéoarthrite de l’American College of Rheumatology. L’auteur accorde une attention spéciale à la thérapie manuelle, à l’exercice physique et à l’information au patient dans le traitement de l’OA du genou et de la hanche. Les auteurs passent en revue le programme Good Life with osteoArthritis in Denmark (GLA:D

Background Joint hypermobility in athletes is associated with increased risk of knee injuries, but its role in relation to shoulder injuries has not been scrutinized. Therefore, our aim was to synthesize the evidence on the association between joint hypermobility and shoulder injuries in athletes. Methods Data sources were MEDLINE, CINAHL, EMBASE, and SPORTDiscus from inception to 27th February 2021. Eligibility criteria were observational studies of athletes (including military personnel), mean age ≥ 16 years, and with a transparent grouping of those with and without joint hypermobility. A broad definition of joint hypermobility as the exposure was accepted (i.e., generalised joint hypermobility (GJH), shoulder joint hypermobility including joint instability). Shoulder injuries included acute and overuse injuries, and self-reported pain was accepted as a proxy for shoulder injuries. The Odds Ratios (OR) for having shoulder injuries in exposed compared with non-exposed athletes were estimated using a random effects meta-analysis. Subgroup analyses were performed to explore the effect of sex, activity type, sports level, study type, risk of bias, and exposure definition. Risk of bias and the overall quality of evidence were assessed using, respectively, the Newcastle–Ottawa Scale and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results Among 6207 records, six studies were included with 2335 (range 118–718) participants (34.1% females; athlete mean age 19.9 years). Athletes with joint hypermobility were more likely to have shoulder injuries compared with athletes without joint hypermobility (OR = 3.25, 95% CI 1.64, 6.43, I2 = 75.3%; p = 0.001). Exposure definition (GJH, OR = 1.97, 95% CI 1.32, 2.94; shoulder joint hypermobility, OR = 8.23, 95% CI 3.63, 18.66; p = 0.002) and risk of bias (low, OR = 5.25, 95% CI 2.56, 10.8; high, OR = 1.6, 95% CI 0.78, 3.29; p = 0.024) had large impacts on estimates, while the remaining subgroup analyses showed no differences. The overall quality of evidence was low. Conclusion Joint hypermobility in athletes is associated with a threefold higher odds of having shoulder injuries, highlighting the need for prevention strategies in this population. However, due to low quality of evidence, future research will likely change the estimated strength of the association. Protocol registration Open Science Framework registration osf.io/3wrn9.

OBJECTIVE: The aims of this study were to evaluate: the proportion of people reporting symptoms associated with lumbar spinal stenosis (LSS) in primary care programs for knee or hip osteoarthritis (OA) or persistent low back pain (LBP) and; the prevalence of self-reported clinical LSS in these three cohorts, according to two sets of adapted criteria.METHOD: A cross-sectional analysis of baseline data from the Good Life with osteoArthritis in Denmark primary care programs. Self-report LSS symptom questions were administered to participants with knee OA, hip OA, and persistent LBP. The prevalence of eleven LSS symptoms and clinical LSS were calculated for each cohort.RESULTS: A total of 10,234 participants were included in the analysis. A similar proportion of participants in each cohort were female (69%), with a 6- and 7-year older mean age in the knee and hip cohorts compared to the back cohort. A greater proportion of participants with LBP reported LSS symptoms (range 11-71%) than in the hip (11-50%) and knee (8-40%) cohorts. This pattern was observed for all but one symptom. The same pattern was observed for the prevalence of clinical LSS with less than 10% of people in each cohort satisfying the clinical criteria.CONCLUSION: Self-reported LSS symptoms are commonly reported by people treated in primary care for knee or hip OA, although not as frequently as reported by those with LBP. Despite symptoms of LSS being common, only a small proportion of people were classified as having self-reported clinical LSS.

Background The detection of prostate cancer requires histological confirmation in biopsy core. Currently, number of unnecessary prostate biopsies are being performed in the United States. This is due to the absence of appropriate biopsy decision‐making protocol. Aim To develop and validate a 4K score/multiparametric magnetic resonance imaging (mpMRI)‐based nomogram to predict prostate cancer (PCa), clinically significant prostate cancer (csPCa), and unfavorable prostate cancer (uPCa). Methods and Results Retrospective, single‐center study evaluating a cohort of 574 men with 4K score test >7% or suspicious digital rectal examination (DRE) or Prostate Imaging Reporting and Data System (PI‐RADS) scores 3, 4, or 5 on mpMRI that underwent systematic and/or mpMRI/ultrasound fusion–targeted prostate biopsy between 2016 and 2020. External cohort included 622 men. csPCa and uPCa were defined as Gleason score ≥3 + 4 and ≥4 + 3 on biopsy, respectively. Multivariable logistic regression analysis was performed to build nomogram for predicting PCa, csPCa, and uPCa. Validation was performed by plotting the area under the curve (AUC) and comparing nomogram‐predicted probabilities with actual rates of PCa, csPCa, and uPCa probabilities in the external cohort. 4K score, a PI‐RADS ≥4, prostate volume and prior negative biopsy were significant predictors of PCa, csPCa, and uPCa. AUCs were 0.84, 0.88, and 0.86 for the prediction of PCa, csPCa, and uPCa, respectively. The predicted and actual rates of PCa, csPCa, and uPCa showed agreement across all percentage probability ranges in the validation cohort. Using the prediction model at threshold of 30, 30% of overall biopsies, 41% of benign biopsies, and 19% of diagnosed indolent PCa could be avoided, while missing 9% of csPCa. Conclusion This novel nomogram would reduce unnecessary prostate biopsies and decrease detection of clinically insignificant PCa.

To determine the incidence and risk factors of musculoskeletal disorders of the elbow in baseball pitchers.Systematic review.Medline, CINAHL, Cochrane, PubMed and SportDiscus from onset to July 7, 2018.Eligible studies included randomized controlled trials, cohort studies and case-control studies. Independent pairs of reviewers screened titles and abstracts for eligibility. Relevant articles were critically appraised for internal validity using the SIGN criteria. We included low risk of bias studies in our best evidence synthesis.We retrieved 4502 articles, 39 were critically appraised and nine had a low risk of bias. These were included in the evidence synthesis. The incidence of musculoskeletal disorders of the elbow ranges from 2.3% in adolescent pitchers to 40.6% in youth pitchers. Evidence suggests that pitch characteristics, inadequate rest, biomechanical and anthropometric factors may be risk factors of UCL tears.Baseball pitchers develop musculoskeletal disorders of the elbow. There is little high-quality evidence to understand the etiology. Preliminary evidence suggests the risk factors are multifactorial.PROSPERO Trial Registration Number: CRD42018092081.Établir l’incidence et facteurs de risque de troubles musculosquelettiques du coude chez le lanceur de baseball.Revue exhaustive.Medline, CINAHL, Cochrane, PubMed et SportDiscus depuis le début jusqu’au 7 juillet 2018.Les études admissibles étaient des essais comparatifs à répartition aléatoire, des études de cohortes et des études de cas-témoins. Des pairs examinateurs indépendants ont trié des titres et des résumés satisfaisant les critères d’admissibilité. On a évalué la validité interne des articles pertinents en utilisant les critères SIGN. On a tenu compte d’un faible risque d’études faussées dans notre meilleure synthèse de preuves.Sur les 4 502 articles retenus, 39 ont été évalués d’une façon critique; neuf présentaient un risque de parti pris. Ceux-ci ont été inclus dans la synthèse de preuves. L’incidence des troubles musculosquelettiques du coude variait de 2,3 % chez les lanceurs adolescents à 40,6 % chez les jeunes lanceurs. Les données semblent indiquer que les caractéristiques du lancer, un repos insuffisant, des facteurs biomécaniques et anthropométriques pourraient être des facteurs de risque de déchirure du ligament collatéral de l’ulna (LCU).Les lanceurs de baseball développent des troubles musculosquelettiques au coude. Il existe peu de preuves de grande qualité permettant de comprendre l’étiologie de ces troubles. Les données préliminaires semblent indiquer que les causes sont multifactorielles.Numéro d’enregistrement d’essai PROSPERO : CRD42018092081.

Objective: Differing clinical criteria for hip osteoarthritis (OA) are applied in primary care, but little is known regarding the utility of these criteria. The aim of this study was to evaluate and compare the proportion of patients in a primary care setting with hip OA fulfilling the American College of Rheumatology (ACR), the National Institute for Health and Care Excellence (NICE), and the Danish Health Authority (DHA) criteria. Design:A cross-sectional analysis of baseline data from the Good Life with osteoArthritis in Denmark (GLA:D®) program, a treatment program for patients with symptoms or functional limitations associated with hip OA. The prevalence of hip OA according to the ACR, NICE, and DHA criteria was calculated in all patients and in a subgroup of patients with self-reported radiographic hip OA. Results: 4699 patients were included in the analysis. Mean age (SD) was 66.8 (9.7) years and 71% of the patients were female. 64%, 80%, and 94% fulfilled the ACR, DHA, and NICE criteria, respectively. In those self-reporting radiographic hip OA, the corresponding numbers were 66%, 81%, and 94%. A limited number of patients (4%) did not fulfill any of the criteria. Conclusions: The NICE criteria identified the most patients that were treated because of their symptoms or functional limitations. The DHA and especially the ACR criteria did not identify a significant proportion of these patients. The results suggest the NICE criteria are appropriate to identify individuals treated for hip OA in primary care.

Background: Elsberg syndrome is a rare cause of lumbosacral radiculitis with concomitant thoracic or lumbosacral myelitis that can be seen following an acute or reactivated viral infection. COVID-19 disease, caused by the SARS-CoV-2 virus, has quickly spread to a global pandemic since its first discovery in the winter of 2019. During this time, there has been an increasing number of case reports describing SARS-CoV-2 associated neuroinflammatory disease.Case Presentation: A 68-year-old man presented in June 2020 with a fall due to progressive lower extremity weakness and numbness, occurring shortly after the initial coronavirus surge in New York City. He developed ascending numbness to the level of the lower abdomen over the preceding month. He subsequently experienced low back pain, and gastrointestinal and genitourinary dysfunction. An extensive laboratory and radiologic evaluation ensued which was notable for elevated SARS-CoV-2 IgG antibodies despite an absence of preceding COVID-19 symptoms. Initial electrodiagnostic testing was notable for absent late responses in the lower extremity nerve conductions with normal distal sensorimotor conductions, and incomplete muscle activation with otherwise normal motor unit morphology and recruitment on electromyography. Repeat testing two weeks later revealed similar nerve conductions, but also the interval development of active neurogenic changes and reduced motor unit recruitment in the L3-L4 myotomes. This was suggestive of a lower thoracic and lumbosacral myelopathy and lumbosacral polyradiculopathy without peripheral neuropathy. A diagnosis of Elsberg syndrome was made and treatment with intravenous methylprednisolone yielded mild clinical improvement and the electrodiagnostic re-emergence of the lower extremity late responses.Conclusions: We report here, to our knowledge, the first case of suspected COVID-19 associated Elsberg syndrome, which may help to shed light on ways in which to approach diagnostic and treatment options in COVID-19 patients presenting with uncommon neurological and autonomic manifestations.

Background Lumbar spinal stenosis (LSS) and knee and hip osteoarthritis (OA) are prevalent conditions in the aging population and published literature suggests they share many symptoms and often are present at the same time in patients. However, no prevalence estimates of multimorbid LSS and knee and/or hip OA are currently available. The primary objective of this systematic review is therefore to estimate the prevalence of multimorbid LSS with knee and/or hip OA using radiological, clinical, and combined case definitions. Methods This systematic review protocol has been designed according to the guidelines from the Cochrane Collaboration and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. A comprehensive search will be performed in the following databases: MEDLINE, EMBASE, CENTRAL, and CINAHL. Forward citation tracking will be performed in Web of Science. No restriction for publication date and language will be applied in the literature search, but only articles in English will be included. The search strategy will include the following domains: LSS, knee OA, and hip OA. Retrieved citations will be screened by two authors independently. Disagreements will be discussed until consensus, and a third reviewer will be consulted if consensus cannot be reached. Data extraction and assessment of risk of bias assessment will be done by two authors independently, using a standardized data extraction form and a modified risk of bias tool for prevalence studies. Meta-analysis estimating prevalence with 95% CI will be performed using a random effects model. Meta-regression analyses will be performed to investigate the impact of the following covariates: LSS clinical presentations, sample population, healthcare setting, risk of bias, and other patient characteristics on prevalence estimates for multimorbid LSS and knee and/or hip OA. Discussion The results of this review will provide the first estimates of the prevalence of multimorbid LSS and hip and knee OA based on various case definitions. The impact of covariates such as LSS clinical presentations, sample population, healthcare setting, risk of bias, and patient characteristics on prevalence estimates will also be presented. Systematic review registration PROSPERO, awaiting registration

PURPOSE: Compare the detection rate of seizures on scalp EEG with simultaneous intracranial stereo EEG (SEEG) recordings. METHODS: Twenty-seven drug-resistant epilepsy patients undergoing SEEG with simultaneous scalp EEG as part of their surgical work-up were included. A total of 172 seizures were captured. RESULTS: Of the 172 seizures detected on SEEG, 100 demonstrated scalp ictal patterns. Focal aware and subclinical seizures were less likely to be seen on scalp, with 33% of each observed when compared with focal impaired aware (97%) and focal to bilateral tonic–clonic seizures (100%) (P < 0.001). Of the 72 seizures without ictal scalp correlate, 32 demonstrated an abnormality during the SEEG seizure that was identical to an interictal abnormality. Seizures from patients with MRI lesions were statistically less likely to be seen on scalp than seizures from nonlesional patients (P = 0.0162). Stereo EEG seizures not seen on scalp were shorter in duration (49 seconds) compared with SEEG seizures seen on scalp (108.6 seconds) (P < 0.001). CONCLUSIONS: Scalp EEG is not a sensitive tool for the detection of focal aware and subclinical seizures but is highly sensitive for the detection of focal impaired aware and focal to bilateral tonic–clonic seizures. Longer duration of seizure and seizures from patients without MRI lesions were more likely to be apparent on scalp. Abnormalities seen interictally may at times represent an underlying seizure. The cognitive, affective, and behavioral long-term effects of ongoing difficult-to-detect seizures are not known.

Objective The electroencephalographic (EEG) terms "brief potentially ictal rhythmic discharges" (BIRDs) and "paroxysmal fast activity" (PFA) are considered distinct entities; however, their definitions overlap, and they may have similar clinical significance. We investigated their clinical significance and their association with seizures and the seizure onset zone (SOZ). Methods We retrospectively identified an adult cohort (July 2015 to March 2018) whose long-term (>12 h) EEGs in any setting reported BIRDs (>4 Hz, lasting .5-10 s) and/or PFA. Different frequency cutoffs for PFA (>13 Hz or ≥8 Hz) were tested to compare their clinical significance. Patient demographics, clinical history, and EEG features were recorded. Results We identified 94 patients with BIRDs/PFA out of 3520 patients (3%); 36 were critically ill (12 with epilepsy), and 58 were noncritically ill (all with epilepsy). The frequency of BIRDs/PFA was largely dependent on EEG background: it tended to be slower (theta) in the absence of a posterior dominant rhythm or in the presence of continuous focal slowing in the same region (p = .01). Sixty-two of 94 patients (66%; 32/36 [89%] critically ill, 30/58 [52%] noncritically ill) had electrographic seizures during the recording. The scalp EEG SOZ colocalized with BIRDs/PFA in all cases. BIRDs with faster frequency (also qualifying as PFA by definition) had similar seizure risk to that of slower BIRDs (62%-71%), regardless of frequency cutoff used to define PFA. In addition, 30 of 30 (100%) patients with evolving BIRDs/PFA (which lasted a median of 6 s, range = 2-9.5 s) had electrographic seizures (>10 s), compared to 32 of 64 (50%) with nonevolving BIRDs (median = 1 s, range = .5-3.5 s; p Significance A high proportion of patients with BIRDs/PFA had seizures on EEG, regardless of their frequency (i.e., whether they also qualified as PFA), and their location colocalized with scalp SOZ in all cases. BIRDs appear to be a scalp EEG biomarker of uncontrolled seizure activity and a reliable localizing sign of the SOZ.

BACKGROUND: There is a paucity of data in the literature specific to men with epilepsy on anti-seizure medication (ASM). The current study investigated the time to conception as well as the gestational and the neurodevelopmental outcomes of offspring of men with epilepsy on ASM compared to controls. Additionally, the prevalence of psychiatric comorbidities, and measures of sexual performance in males with and without epilepsy were analyzed. METHODS: A total of 450 male patients with and without epilepsy at one hospital were provided questionnaires to determine demographic characteristics, epilepsy history, type of ASM at the time of conception, comorbidities and sexual health. Time to conception, fertility methods and offspring birth and developmental history born to males with and without epilepsy was recorded. Survey data was evaluated using Student’s t-test for continuous variables and Fisher’s exact test for categorical variables. Odds ratio (OR) were calculated to determine associations between the measured data. RESULTS: After matching for age, we analyzed a total of 110 males with epilepsy and 110 without epilepsy. In the epilepsy group there was a higher rate of psychiatric comorbidities such as major depressive disorder, general anxiety disorder, bipolar disorder, and suicidal ideation when compared to the control group (N = 110; OR 3.39; 95% IC: 1.87–6.13, p < 0.001). Males with epilepsy also had a higher frequency of low erection scores when compared to males without epilepsy (N = 70 with epilepsy, N = 76 without epilepsy; OR 3.67; 95% IC: 1.44–9.39, p = 0.005). Of the 110 men with a diagnosis of epilepsy, 17 conceived children while using ASMs (38 total children). A total of 18.42% of children born to fathers on ASMs experienced developmental delays compared to 2.63% of controls, however this result was not statistically significant (p = 0.056). In addition, we did not find that offspring had significantly different birth weights or gestational ages in men on ASM compared to controls (p > 0.05). CONCLUSIONS: The present study suggests that men with epilepsy have an increased incidence of psychiatric comorbidities, and altered sexual performance, specifically erectile dysfunction, when compared with men without epilepsy. There was no statistically significant difference in the rates of developmental disorders and birth characteristics among those men with epilepsy on ASM at the time of conception and controls.

The mechanism of amobarbital action during the intracarotid amobarbital procedure is poorly understood. We report a patient case who underwent IAP while implanted with bilateral stereo-EEG. We analyzed the spectral power, phase amplitude coupling, and cluster-phase group synchrony during the procedure. Delta and gamma power increased bilaterally. By contrast, phase amplitude coupling increased only ipsilateral to the injection. Similarly, 4–30 Hz cluster-phase group synchrony declines and gamma cluster-phase group synchrony increases only ipsilateral to the injection. These results suggest that a possible additional mechanism for amobarbital action in the IAP is by altering the precise timing of oscillatory activity., Highlights • Intracranial activity shows bilateral increases in delta and gamma activity during the IAP. • Phase amplitude coupling increases in the 2–3 Hz (phase) and 30–70 Hz (amplitude) band only ipsilateral to the injection. • 4–30 Hz synchrony declines and gamma synchrony increases only ipsilateral to the injection. • Amobarbital may alter the temporal organization of activity, rather than inactivation of the injected hemisphere.

Degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD) causes motor dysfunction and cognitive impairment, but the etiology of the cognitive deficits remains unclear. The present study investigated the behavioral effects of partial lesions of the nigrostriatal dopamine (DA) pathway. Rats received bilateral infusions of either 6-hydroxydopamine (6-OHDA) or vehicle into the dorsolateral striatum and were tested in spatial and procedural learning tasks. Compared with intact rats, DA-depleted rats were impaired when the first task they learned required egocentric responses. Intact rats that received prior training on a spatial task were impaired while learning a subsequent body-turn task, suggesting that prior spatial training may compete with egocentric learning in intact but not DA-depleted rats. Spatial discrimination, reversal learning, and switching between allocentric and egocentric strategies were similar in both groups. The results suggest that DA loss that is not associated with gross motor pathology temporarily impairs egocentric, but not allocentric, learning or subsequent behavioral flexibility. (PsycINFO Database Record

Summary Objective To determine and compare the proportion of patients treated in a primary care setting that have knee osteoarthritis (OA) according to the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the National Institute for Health and Care Excellence (NICE) clinical classification criteria. Design A cross-sectional analysis of baseline data from 13,459 patients with knee symptoms or functional limitations associated with OA participating in the Good Life with osteoArthritis in Denmark (GLA:D®) treatment program. The prevalence of knee OA according to the EULAR, ACR and NICE criteria were calculated in all participants and in the subgroup of patients with self-reported radiographic changes associated with knee OA (n = 10,651 or 79%). Results Mean age (SD) was 65.3 (9.8) years, median (IQR) duration of symptoms 12 (6–36) months and mean pain intensity (0–100; SD) 46.5 (22.1) mm. 39% fulfilled all three sets of criteria. 48%, 52% and 89% fulfilled the EULAR, ACR, and NICE criteria for having knee OA, respectively. In the subgroup with self-reported radiographic changes, the corresponding numbers were 49%, 54% and 90%. Conclusions While the EULAR and ACR criteria only identified around half of those, with or without self-reported radiographic knee OA, that were treated because of symptoms or functional limitations associated with knee OA, the NICE criteria identified most patients. The results indicate that the NICE criteria are relevant and appropriate to identify individuals treated for knee OA in primary care.

The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not., eLife digest The brain has the ability to adapt after injury, a process known as plasticity. When one area sustains damage, for example following a car accident or stroke, other areas change their activity and structure to compensate. Understanding how this happens is critical to helping people recover from brain injuries. Certain factors may affect how well the brain can repair itself. These include how much the damaged area interacts with other areas, and which cell types different areas of the brain contain. Froudist-Walsh et al. set out to determine how these factors influence recovery from brain injury in monkeys, whose brains are similar to our own. The monkeys had damage to a structure called the hippocampus. This part of the brain has a key role in memory, which is often impaired in patients with brain injuries. The hippocampus cannot repair itself because the brain has only a limited capacity to grow new neurons. Instead, the brain attempts to compensate for disruption to the hippocampus via changes in other, undamaged areas. Using brain imaging, Froudist-Walsh et al. show that the types of changes that occur depend on how much time has passed since the injury. In the first three months, many areas of the brain change how much they coordinate their activity with other areas. Highly connected areas reduce their communication with other areas the most. In the long-term, the responses of brain areas depend more on which cell types they contain. Areas with more support cells known as “glia” – which supply nutrients and energy to neurons – are better able to adapt their connectivity up to a year after the injury. These findings may ultimately benefit people who have suffered brain injuries after accidents or stroke. They suggest that stimulating intact brain areas may be helpful in the months immediately after an injury. By contrast, long-term therapy may need to focus more on structural repair. Future studies must build on these results to discover the best ways to induce successful recovery from brain injury.

Direct electrical stimulation (DES) is sometimes used in epilepsy surgery to identify areas that may result in language deficits if resected. Extraoperative language mapping is usually performed using electrocorticography (ECOG) - grids and strip electrodes; however, given the better safety profile of stereoelectroencephalogaphy (SEEG), it would be desirable to determine if mapping using SEEG is also effective. We report a case series of fifteen patients that underwent language mapping with either ECOG (5), SEEG (9), or both (1). Six patients in the SEEG group underwent resection or ablation with only mapping via SEEG. No patients in the SEEG group that underwent resective or ablative surgery experienced persistent language deficits. These results suggest that language mapping with SEEG may be considered as a clinically useful alternative to language mapping with ECOG.

Episodic memory, everyday memory for events, is frequently impaired in patients with epilepsy. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the treatment of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. We report that an anatomically diffuse network characterized by theta-band (4–7 Hz) coherence is activated at the time of target selection in a task that requires episodic memory. This distinct network of oscillatory activity is absent when episodic memory is not required. Further, the theta band synchronous network was absent in electrodes within the patient's seizure onset zone (SOZ). Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans, and it provides a pathophysiologic mechanism for the memory deficits observed in patients with epilepsy.

Episodic memory, everyday memory for events, is fundamental to our lives. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the localization of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. Here we report that an anatomically diffuse network characterized by thetaband (4-7 Hz) coherence is activated at the time of a choice that requires episodic memory. This distinct network pattern of oscillatory activity is absent in situations that do not require episodic memory. The episodic network we identified spans prefrontal and temporal lobes and coherence between these areas was greatest during memory encoding. Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans.Significance StatementSynchronous oscillations of electrical fields are thought to support brain processes such as language, movement, memory and learning. However, little is known about which types of synchronous oscillations are needed for which process. We performed invasive recordings of electrical activity in patients undergoing surgical management for epilepsy while they perform different types of memory tasks. We found synchronous oscillations in the theta band (4-7 Hz) correlate with performance in an episodic memory. This pattern of oscillations activates a distinct network of brain regions from a task that does not require episodic memory. This finding advances our understanding of the brain systems that support each process.

Orbitofrontal cortex (OFC) function is often characterized in terms of stimulus-reward mapping; however, more recent evidence suggests that the OFC may play a role in selecting and representing extended actions. First, previously encoded reward associations in the OFC could be used to inform responding in novel but similar situations. Second, when evaluated in tasks requiring the animal to perform extended actions, response selective activity can be recorded in the OFC. Finally, the interaction between the OFC and hippocampus illustrates OFC's role in response selection. The OFC may facilitate reward-guided memory retrieval by selecting the memories most relevant to achieve a goal. This model for OFC function places it within the hierarchy of increasingly complex action representations that support decision making.

Adapting successfully to new situations relies on integrating memory of similar circumstances with the outcomes of past actions. Here, we tested how reward history and recent memory influenced coding by orbital prefrontal cortex (OFC) neurons. Rats were trained to find food in plus maze tasks that required both the OFC and the hippocampus, and unit activity was recorded during stable performance, reversal learning, and strategy switching. OFC firing distinguished different rewarded paths, journeys from a start arm to a goal arm. Activity of individual cells and the population correlated with performance as rats learned newly rewarded outcomes. Activity was similar during reversal, an OFC-dependent task, and strategy switching, an OFC-independent task, suggesting that OFC associates information about paths and outcomes both when it is required for performance and when it is not. Path-selective OFC cells fired differently during overlapping journeys that led to different goals or from different starts, resembling journey-dependent coding by hippocampal neurons. Local field potentials (LFPs) recorded simultaneously in the OFC and the hippocampus oscillated coherently in the theta band (5–12 Hz) during stable performance. LFP coherence diminished when rats adapted to altered reward contingencies and followed different paths. Thus, OFC neurons appear to participate in a distributed network including the hippocampus that associates spatial paths, recent memory, and integrated reward history.

Prelimbic-infralimbic cortex (PL-IL) and orbitofrontal cortex (OFC) influence behavioral flexibility in the rat. The authors tested the effects of PL-IL or OFC infusion with the GABA agonist muscimol in the context of 2 flexible responding tasks: strategy switching and reversal. Muscimol infusion into PL-IL impaired retention of strategy switches but not reversals, whereas muscimol infusion into OFC impaired retention of reversals but not switches. However, whereas training in repeated reversals did not remove the requirement of PL-IL for switch retention (E. L. Rich & M. L. Shapiro, 2007), training in repeated switches did remove the requirement of OFC for reversal retention. Thus, activity during strategy switches was sufficient to initiate learning and remove the requirement of OFC in later reversals.

Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase beta/zeta (RPTPbeta), we postulated that simultaneous binding of MAGI proteins to RPTPbeta and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPbeta. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPbeta for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n= approximately 1400). PTPRZ1, which codes for RPTPbeta, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P=0.0003; gene-wide P=0.0064; hypothesis-wide P=0.026). The data provide evidence for a role of PTPRZ1, and for RPTPbeta signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPbeta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.