Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry.

In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.

High-resolution 1H-MRSI at 9.4 T by integrating relaxation enhancement and subspace imaging.

Achieving high-resolution and high signal-to-noise ratio (SNR) in vivo metabolic imaging via fast magnetic resonance spectroscopic imaging (MRSI) has been a longstanding challenge. This study combines the methods of relaxation enhancement (RE) and subspace imaging for the first time, enabling high-resolution and high-SNR in vivo MRSI of rodent brains at 9.4 T. Specifically, an RE-based chemical shift imaging sequence, which combines a frequency-selective pulse to excite only the metabolite frequencies with minimum perturbation of the water spins and a pair of adiabatic pulses to spatially localize the slice of interest, is designed and evaluated in vivo. This strategy effectively shortens the apparent T1 of metabolites, thereby increasing the SNR during relatively short repetition time ((TR) compared with acquisitions with only spatially selective wideband excitations, and does not require water suppression. The SNR was further enhanced via a state-of-the-art subspace reconstruction method. A novel subspace learning strategy tailored for 9.4 T and RE acquisitions is developed. In vivo, high-resolution (e.g., voxel size of 0.6 × 0.6 × 1.5 mm3) MRSI of both healthy mouse brains and a glioma-bearing mouse brain in 12.5 min has been demonstrated.

Patterns, timing and predictors of recurrence following pancreaticoduodenectomy for distal cholangiocarcinoma: An international multicentre retrospective cohort study.

INTRODUCTION: Patients undergoing pancreaticoduodenectomy for distal cholangiocarcinoma (dCCA) often develop cancer recurrence. Establishing timing, patterns and risk factors for recurrence may help inform surveillance protocol strategies or select patients who could benefit from additional systemic or locoregional therapies. This multicentre retrospective cohort study aimed to determine timing, patterns, and predictive factors of recurrence following pancreaticoduodenectomy for dCCA. MATERIALS AND METHODS: Patients who underwent pancreaticoduodenectomy for dCCA between June 2012 and May 2015 with five years of follow-up were included. The primary outcome was recurrence pattern (none, local-only, distant-only or mixed local/distant). Data were collected on comorbidities, investigations, operation details, complications, histology, adjuvant and palliative therapies, recurrence-free and overall survival. Univariable tests and regression analyses investigated factors associated with recurrence. RESULTS: In the cohort of 198 patients, 129 (65%) developed recurrence: 30 (15%) developed local-only recurrence, 44 (22%) developed distant-only recurrence and 55 (28%) developed mixed pattern recurrence. The most common recurrence sites were local (49%), liver (24%) and lung (11%). 94% of patients who developed recurrence did so within three years of surgery. Predictors of recurrence on univariable analysis were cancer stage, R1 resection, lymph node metastases, perineural invasion, microvascular invasion and lymphatic invasion. Predictors of recurrence on multivariable analysis were female sex, venous resection, advancing histological stage and lymphatic invasion. CONCLUSION: Two thirds of patients have cancer recurrence following pancreaticoduodenectomy for dCCA, and most recur within three years of surgery. The commonest sites of recurrence are the pancreatic bed, liver and lung. Multiple histological features are associated with recurrence.

A bacteriophage-based validation of a personal protective equipment doffing procedure to be used with high-consequence pathogens.

OBJECTIVE: To determine if the high-level personal protective equipment used in the treatment of high-consequence infectious diseases is effective at stopping the spread of pathogens to healthcare personnel (HCP) while doffing. BACKGROUND: Personal protective equipment (PPE) is fundamental to the safety of HCPs. HCPs treating patients with high-consequence infectious diseases use several layers of PPE, forming complex protective ensembles. With high-containment PPE, step-by-step procedures are often used for donning and doffing to minimize contamination risk to the HCP, but these procedures are rarely empirically validated and instead rely on following infection prevention best practices. METHODS: A doffing protocol video for a high-containment PPE ensemble was evaluated to determine potential contamination pathways. These potential pathways were tested using fluorescence and genetically marked bacteriophages. RESULTS: The experiments revealed existing protocols permit contamination pathways allowing for transmission of bacteriophages to HCPs. Updates to the doffing protocols were generated based on the discovered contamination pathways. This updated doffing protocol eliminated the movement of viable bacteriophages from the outside of the PPE to the skin of the HCP. CONCLUSIONS: Our results illustrate the need for quantitative, scientific investigations of infection prevention practices, such as doffing PPE.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89%, 99:1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5)- and C(6)-position, as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O•••isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)-, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Intermittent Hypoxia-Induced Enhancements in Corticospinal Excitability Predict Gains in Motor Learning and Metabolic Efficiency.

Acute intermittent hypoxia (AIH) enhances human motor function after incomplete spinal cord injury. Although the underlying mechanisms in humans are unknown, emerging evidence indicates that AIH facilitates corticospinal excitability to the upper limb. However, the functional relevance of this plasticity remains unexplored, and it is unclear whether similar plasticity can be induced for lower limb motor areas. We recently demonstrated that AIH improves motor learning and metabolic efficiency during split-belt walking. Thus, we hypothesized that AIH increases lower limb excitability and that these enhancements would predict the magnitude of motor learning and the corresponding reductions in net metabolic power. We assessed tibialis anterior (TA) excitability using transcranial magnetic stimulation and quantified changes in spatiotemporal asymmetries and net metabolic power in response to split-belt speed perturbations. We show that AIH enhances TA excitability, and that the magnitude of this facilitation positively correlates with greater spatiotemporal adaptation. Notably, we demonstrate a novel association between increased excitability and reduced net metabolic power during motor learning and savings. Together, our results suggest that AIH-induced gains in excitability predict both the magnitude of motor learning and the associated metabolic efficiency. Determining indices of AIH-induced improvements in motor performance is critical for optimizing its therapeutic reach.

Distinct clinical endpoints of Staphylococcus aureus bacteraemia complicate assessment of outcome.

BACKGROUND: We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to SAB. METHODS: We conducted a retrospective observational study of adults with SAB between 20/12/2019 and 23/08/2022 (n=464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical and microbiologic features. RESULTS: Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14·4% of cohort), metastatic SAB (without attributable mortality, 22·2%), neither complication (56·7%), and overlapping fatal/metastatic SAB (6·7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteraemia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset. CONCLUSIONS: Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality vs. improve clinical response in patients with metastatic SAB.

Monolithic Zirconia Single Crowns Supported by Narrow or Standard Diameter Titanium-zirconium Implants in Posterior Sites: One-year Results of a Randomized Controlled Trial.

The replacement of missing teeth with implant-supported prostheses has become a standard treatment option with reliable long-term outcomes in various clinical indications.1-6 The implant-supported single crowns, in particular, presented the most favorable outcome with a survival rate of 89.5% to 96% over a 10-year period.5,6 A notable prosthetic maintenance requirement, however, was reported irrespective of the prosthetic material used for the crown construction.1,7 Metal-ceramic restorations have been considered the gold standard when replacing single or multiple missing teeth with implant-supported fixed dental prostheses.8 A systematic review of 4363 metal-ceramic implant-supported single crowns in the anterior and posterior region reported an impressive survival rate of 98.3% over five years.9 Yet, the biologic and prosthetic complications associated with these restorations were substantial with a rate of 13.5%. In the posterior region, a recent systematic review of short-term randomized controlled trials10 reported a survival rate of 99.1% for metal-ceramic implant-supported single crowns. The reported prosthetic complications, mainly ceramic chipping, were also notable with an incidence rate of 7.6%.mIn recent years, the introduction of high-strength all-ceramic materials as well as digitaldesign and manufacturing processes, has allowed faster fabrication of more esthetic and cost effective restorations.11 Zirconia-based fixed dental prostheses on teeth and implants are now increasingly used and show 5-year cumulative survival rates of 89.4 to 100%.12 These restorations are typically made up of a zirconia framework that is veneered with a layer of glass ceramic to impart translucency for enhanced esthetics.13 However, chipping of the ceramic layer has been a lingering issue, shifting the attention toward the use of full anatomic monolithic zirconia restorations.14,15 Replacement of missing teeth with dental implants in posterior ridges with limited bone width can be surgically challenging and the notion of narrow diameter implants has been suggested.16,17 These implants were thought to offer potential advantages in terms of costeffectiveness and surgical morbidity.18,19 The literature, however, remains controversial on treatment outcomes with narrow diameter implants, particularly in posterior sites.19-21 When single tooth replacement with monolithic zirconia implant-supported single crowns in posterior sites are considered, only short to medium-term outcomes are available.22-26 The survival rates and clinical performances reported in these studies were variable. Crown survival rates between 84% and 100% were demonstrated over an observation time of one to three years, while the prosthetic complications were between 0% to 14%. In three studies,22,23,25 standard diameter titanium implants were used in premolar and molar sites to support the single crowns. The remaining two studies by Mühlemann et al. (2020) and Zumstein et al. (2023) reported the one-year and three-year outcomes, respectively, of the same cohort. In these studies, narrow titanium-zirconium (TiZr) implants of 3.3 mm diameter were exclusively utilized in molar sites. The implant and crown survival rates reported at one and three years were 97.4% and 84%, respectively. The lower survival rate observed in the report of Zumstein et al. (2023) resulted from fracture of five implants and the subsequent loss of their respective crowns. Aside from these two reports, no other information on the outcomes of monolithic zirconia single crowns supported by narrow diameter TiZr implants in posterior sites are available. The validity of this treatment, therefore, needs further investigation with well-designed clinical trials. Hence, a randomized controlled trial was undertaken to assess various implant, prosthetic, and patient-reported outcomes of monolithic zirconia single crowns supported by either narrow or standard diameter titanium-zirconium (TiZr) implants in posterior sites. The present report focuses on the one-year prosthetic results.

Five-year recurrence/survival after pancreatoduodenectomy for pancreatic adenocarcinoma: does pre-existing diabetes matter? Results from the Recurrence After Whipple's (RAW) study.

BACKGROUND: Diabetes mellitus (DM) has a complex relationship with pancreatic cancer. This study examines the impact of preoperative DM, both recent-onset and pre-existing, on long-term outcomes following pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multi-centre cohort of PD for pancreatic head malignancy (2012-2015). Recurrence and five-year survival rates of patients with DM were compared to those without, and subgroup analysis performed to compare patients with recent-onset DM (less than one year) to patients with established DM. RESULTS: Out of 758 patients included, 187 (24.7%) had DM, of whom, 47 of the 187 (25.1%) had recent-onset DM. There was no difference in the rate of postoperative pancreatic fistula (DM: 5.9% vs no DM 9.8%; p = 0.11), five-year survival (DM: 24.1% vs no DM: 22.9%; p = 0.77) or five-year recurrence (DM: 71.7% vs no DM: 67.4%; p = 0.32). There was also no difference between patients with recent-onset DM and patients with established DM in postoperative outcomes, recurrence, or survival. CONCLUSION: We found no difference in five-year recurrence and survival between diabetic patients and those without diabetes. Patients with pre-existing DM should be evaluated for PD on a comparable basis to non-diabetic patients.

Impact of organic phosphates on the structure and composition of short-range ordered iron nanophases.

Organic phosphates (OP) are important nutrient components for living cells in natural environments, where they readily interact with ubiquitous iron phases such as hydrous ferric oxide, ferrihydrite (FHY). FHY partakes in many key bio(geo)chemical reactions including iron-mediated carbon storage in soils, or iron-storage in living organisms. However, it is still unknown how OP affects the formation, structure and properties of FHY. Here, we document how ß-glycerophosphate (GP), a model OP ligand, affects the structure and properties of GP-FHY nanoparticles synthesized by coprecipitation at variable nominal molar P/Fe ratios (0.01 to 0.5). All GP-FHY precipitates were characterized by a maximum solid P/Fe ratio of 0.22, irrespective of the nominal P/Fe ratio. With increasing nominal P/Fe ratio, the specific surface area of the GP-FHY precipitates decreased sharply from 290 to 3 m2 g-1, accompanied by the collapse of their pore structure. The Fe-P local bonding environment gradually transitioned from a bidentate binuclear geometry at low P/Fe ratios to monodentate mononuclear geometry at high P/Fe ratios. This transition was accompanied by a decrease in coordination number of edge-sharing Fe polyhedra, and the loss of the corner-sharing Fe polyhedra. We show that Fe(iii) polymerization is impeded by GP, and that the GP-FHY structure is highly dependent on the P/Fe ratio. We discuss the role that natural OP-bearing Fe(iii) nanophases have in biogeochemical reactions between Fe-P and C species in aquatic systems.

Thalamic atrophy and dysconnectivity are associated with cognitive impairment in a multi-center, clinical routine, real-word study of people with relapsing-remitting multiple sclerosis.

BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized ß = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized ß = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

Cardiac transplant rejection assessment with 18F-FDG PET-CT: initial single-centre experience for diagnosis and management.

BACKGROUND: Rejection is a major cause of mortality and morbidity in heart transplant (HTx) recipients. Current methods for diagnosing rejection have limitations. Imaging methods to map the entire left ventricle and reliably identify potential sites of rejection is lacking. Animal studies suggest FDG PET-CT (FDG PET) could have potential application in human HTx recipients. METHODS: Between December 2020 and February 2022, all HTx recipients at Harefield Hospital, London, with definite or suspected rejection underwent FDG PET in addition to routine work-up. RESULTS: Thirty HTx recipients (12 with definite and 18 with suspected rejection) underwent FDG PET scans. Overall, 12 of the 30 patients had FDG PET with increased myocardial avidity, of whom 2 died (17%). Eighteen patients of the 30 patients had FDG PET with no myocardial avidity and all are alive (100%, p = 0.15). All patients with definite rejection, scanned within 2 weeks of starting anti-rejection treatment, showed increased myocardial avidity. In 5 cases, FDG PET showed myocardial avidity beyond 6 weeks despite pulsed steroid treatment, suggesting unresolved myocardial rejection. CONCLUSION: Preliminary findings suggest FDG PET may have a role in diagnosing cardiac transplant rejection. Future blinded studies are needed to help further validate this.

Developing emotional preparedness and mental resilience through high-fidelity simulation: a 'bridge too far' for institutions teaching major trauma management and mass-casualty medicine?

BACKGROUND: Clinical acumen represents only part of being adequately equipped to attend a major incident. The emotive sights, sounds and smells of these dynamic environments are all-encompassing experiences, and responders must also be armed with the emotional preparedness to perform their clinical or managerial duties effectively, as well as the mental resilience to facilitate professional continuance. Despite this, limited training and a sparsity of evidence exists to guide developments within this domain. Historically, major incident training has focused on clinical theory acquisition, but irrespective of how comprehensive the learning materials, they are of little consequence if tandem steps to cultivate mental resilience and emotional preparedness are absent. High-Fidelity Simulation (HFS) has a growing reputation as an effective means of bridging important gaps between theory and practice. This pilot study aimed to measure student's self-reported perception of their readiness to respond to a major incident following a large-scale HFS. METHODS: Quantitative data was obtained from a sample of 108 students undertaking paramedic science, physician associate studies and adult nursing degree programmes. A bespoke questionnaire was developed to measure self-reported clinical acumen, mental and emotional preparedness. RESULTS: 91% of students agreed the combination of theoretical training and HFS provided made them feel clinically prepared to attend a real major incident; 86% agreed this experience had developed their mental resilience and 90% agreed that they felt emotionally prepared to attend a major incident. CONCLUSION: Within this pilot study, the blend of theoretical training and HFS contributed to self-reported clinical acumen, mental and emotional preparation, in learners training to work in disaster environments or emergency medicine settings.

SCIseg: Automatic Segmentation of T2-weighted Intramedullary Lesions in Spinal Cord Injury.

Purpose: To develop a deep learning tool for the automatic segmentation of T2-weighted intramedullary lesions in spinal cord injury (SCI). Material and Methods: This retrospective study included a cohort of SCI patients from three sites enrolled between July 2002 and February 2023. A deep learning model, SCIseg, was trained in a three-phase process involving active learning for the automatic segmentation of intramedullary SCI lesions and the spinal cord. The data consisted of T2-weighted MRI acquired using different scanner manufacturers with heterogeneous image resolutions (isotropic/anisotropic), orientations (axial/sagittal), lesion etiologies (traumatic/ischemic/hemorrhagic) and lesions spread across the cervical, thoracic and lumbar spine. The segmentations from the proposed model were visually and quantitatively compared with other open-source baselines. Wilcoxon signed-rank test was used to compare quantitative MRI biomarkers (lesion volume, lesion length, and maximal axial damage ratio) computed from manual lesion masks and those obtained automatically with SCIseg predictions. Results: MRI data from 191 SCI patients (mean age, 48.1 years ± 17.9 [SD]; 142 males) were used for model training and evaluation. SCIseg achieved the best segmentation performance for both the cord and lesions. There was no statistically significant difference between lesion length and maximal axial damage ratio computed from manually annotated lesions and those obtained using SCIseg. Conclusion: Automatic segmentation of intramedullary lesions commonly seen in SCI replaces the tedious manual annotation process and enables the extraction of relevant lesion morphometrics in large cohorts. The proposed model segments lesions across different etiologies, scanner manufacturers, and heterogeneous image resolutions. SCIseg is open-source and accessible through the Spinal Cord Toolbox.

Analysis of the adhesive secreting cells of Arion subfuscus: insights into the role of microgels in a tough, fast-setting hydrogel glue.

The slug Arion subfuscus produces a tough, highly adhesive defensive secretion. This secretion is a flexible hydrogel that is toughened by a double network mechanism. While synthetic double network gels typically require extensive time to prepare, this slug creates a tough gel in seconds. To gain insight into how the glue forms a double-network hydrogel so rapidly, the secretory apparatus of this slug was analyzed. The goal was to determine how the major components of the glue were distributed and mixed. Most of the glue comes from two types of large unicellular glands; one secretes polyanionic polysaccharides in small, membrane-bound packets, the other secretes proteins that appear to form a cross-linked network. The latter gland shows distinct regions where cross-linking appears to be occurring. These regions are darker, more homogeneous and appear more solid than the rest of the secretory material. The enzyme catalase is highly abundant in these regions, as are basic proteins. These results suggest that a rapid oxidation event occurs in this protein-containing gland, triggering cross-linking before the glue is released. The cross-linked microgels would then join together after secretion to form a granular hydrogel. The polysaccharide-filled packets would be mixed and interspersed among these microgels and may contribute to joining them together. This is an unexpected and highly effective way to form a tough gel rapidly.

Improving access to chronic pain care with central referral and triage: The 6-year findings from a single-entry model.

Background: Despite the established efficacy of multidisciplinary chronic pain care, barriers such as inflated referral wait times and uncoordinated care further hinder patient health care access. Aims: Here we describe the evolution of a single-entry model (SEM) for coordinating access to chronic pain care across seven hospitals in Toronto and explore the impact on patient care 6 years after implementation. Methods: In 2017, an innovative SEM was implemented for chronic pain referrals in Toronto and surrounding areas. Referrals are received centrally, triaged by a clinical team, and assigned an appointment according to the level of urgency and the most appropriate care setting/provider. To evaluate the impact of the SEM, a retrospective analysis was undertaken to determine referral patterns, patient characteristics, and referral wait times over the past 6 years. Results: Implementation of an SEM streamlined the number of steps in the referral process and led to a standardized referral form with common inclusion and exclusion criteria across sites. Over the 6-year period, referrals increased by 93% and the number of unique providers increased by 91%. Chronic pain service wait times were reduced from 299 (±158) days to 176 (±103) days. However, certain pain diagnoses such as chronic pelvic pain and fibromyalgia far exceed the average. Conclusions: The results indicate that the SEM helped reduce wait times for pain conditions and standardized the referral pathway. Continued data capture efforts can help identify gaps in care to enable further health care refinement and improvement.

Contexte: Malgré l'efficacité établie des soins multidisciplinaires dans le traitement de la douleur chronique, des obstacles tels que des délais d'attente prolongés et l'absence de coordination des soins entravent davantage l'accès des patients aux services de santé.Objectifs: Nous décrivons ici l'évolution d'un modèle à entrée unique visant à coordonner l'accès aux soins pour la douleur chronique dans sept hôpitaux de Toronto. Nous examinons également l'effet de ce modèle sur les soins aux patients six ans après sa mise en œuvre.Méthodes: En 2017, un modèle à entrée unique novateur a été mis en place pour orienter les patients souffrant de douleur chronique à Toronto et dans les régions avoisinantes. Les patients sont reçus de manière centralisée, triés par une équipe clinique et un rendez-vous leur est attribué en fonction du degré d'urgence et de l'établissement de soins ou du prestataire le plus approprié.Pour évaluer l'impact du modèle à entrée unique, une analyse rétrospective a été entreprise afin de déterminer les schémas de consultation, les caractéristiques des patients et les temps d'attente pour les demandes de consultation au cours des six dernières années.Résultats: La mise en œuvre d'un modèle à entrée unique a permis de rationaliser le nombre d'étapes du processus de demande de consultation et a conduit à l'élaboration d'un formulaire de demande de consultation normalisé comprenant des critères d'inclusion et d'exclusion communs à tous les sites. Au cours de la période de six ans, le nombre de demandes de consultation a augmenté et le nombre de prestataires uniques a augmenté de 91 %.Les temps d'attente pour les services de traitement de la douleur chronique ont diminué de 299 (±158) jours à 176 (±103) jours. Cependant, certains diagnostics de douleur, comme la douleur pelvienne chronique et la fibromyalgie, dépassent de loin la moyenne.Conclusions: Les résultats indiquent que le modèle à entrée unique a contribué à réduire les temps d'attente pour les affections douloureuses et à normaliser le parcours de consultation. La poursuite des efforts de collecte des données peut aider à recenser les lacunes dans les soins, permettant ainsi une amélioration continue des soins de santé.

Peak Slope Ratio of the Recruitment Curves Compared to Muscle Evoked Potentials to Optimize Standing Configurations with Percutaneous Epidural Stimulation after Spinal Cord Injury.

Background: Percutaneous spinal cord epidural stimulation (pSCES) has effectively restored varying levels of motor control in persons with motor complete spinal cord injury (SCI). Studying and standardizing the pSCES configurations may yield specific motor improvements. Previously, reliance on the amplitude of the SCES-evoked potentials (EPs) was used to determine the correct stimulation configurations. Methods: We, hereby, retrospectively examined the effects of wide and narrow-field configurations on establishing the motor recruitment curves of motor units of three different agonist-antagonist muscle groups. Magnetic resonance imaging was also used to individualize SCI participants (n = 4) according to their lesion characteristics. The slope of the recruitment curves using a six-degree polynomial function was calculated to derive the slope ratio for the agonist-antagonist muscle groups responsible for standing. Results: Axial damage ratios of the spinal cord ranged from 0.80 to 0.92, indicating at least some level of supraspinal connectivity for all participants. Despite the close range of these ratios, standing motor performance was enhanced using different stimulation configurations in the four persons with SCI. A slope ratio of ≥1 was considered for the recommended configurations necessary to achieve standing. The retrospectively identified configurations using the supine slope ratio of the recruitment curves of the motor units agreed with that visually inspected muscle EPs amplitude of the extensor relative to the flexor muscles in two of the four participants. Two participants managed to advance the selected configurations into independent standing performance after using tonic stimulation. The other two participants required different levels of assistance to attain standing performance. Conclusions: The findings suggest that the peak slope ratio of the muscle agonists-antagonists recruitment curves may potentially identify the pSCES configurations necessary to achieve standing in persons with SCI.

White matter tracts adjacent to the human cingulate sulcus visual area (CSv).

Human cingulate sulcus visual area (CSv) was first identified as an area that responds selectively to visual stimulation indicative of self-motion. It was later shown that the area is also sensitive to vestibular stimulation as well as to bodily motion compatible with locomotion. Understanding the anatomical connections of CSv will shed light on how CSv interacts with other parts of the brain to perform information processing related to self-motion and navigation. A previous neuroimaging study (Smith et al. 2018, Cerebral Cortex, 28, 3685-3596) used diffusion-weighted magnetic resonance imaging (dMRI) to examine the structural connectivity of CSv, and demonstrated connections between CSv and the motor and sensorimotor areas in the anterior and posterior cingulate sulcus. The present study aimed to complement this work by investigating the relationship between CSv and adjacent major white matter tracts, and to map CSv's structural connectivity onto known white matter tracts. By re-analysing the dataset from Smith et al. (2018), we identified bundles of fibres (i.e. streamlines) from the whole-brain tractography that terminate near CSv. We then assessed to which white matter tracts those streamlines may belong based on previously established anatomical prescriptions. We found that a significant number of CSv streamlines can be categorised as part of the dorsalmost branch of the superior longitudinal fasciculus (SLF I) and the cingulum. Given current thinking about the functions of these white matter tracts, our results support the proposition that CSv provides an interface between sensory and motor systems in the context of self-motion.

The effectiveness of abstinence-based and harm reduction-based interventions in reducing problematic substance use in adults who are experiencing homelessness in high income countries: A systematic review and meta-analysis: A systematic review.

Background: Homelessness is a traumatic experience, and can have a devastating effect on those experiencing it. People who are homeless often face significant barriers when accessing public services, and have often experienced adverse childhood events, extreme social disadvantage, physical, emotional and sexual abuse, neglect, low self-esteem, poor physical and mental health, and much lower life expectancy compared to the general population. Rates of problematic substance use are disproportionately high, with many using drugs and alcohol to deal with the stress of living on the street, to keep warm, or to block out memories of previous abuse or trauma. Substance dependency can also create barriers to successful transition to stable housing. Objectives: To understand the effectiveness of different substance use interventions for adults experiencing homelessness. Search Methods: The primary source of studies for was the 4th edition of the Homelessness Effectiveness Studies Evidence and Gaps Maps (EGM). Searches for the EGM were completed in September 2021. Other potential studies were identified through a call for grey evidence, hand-searching key journals, and unpacking relevant systematic reviews. Selection Criteria: Eligible studies were impact evaluations that involved some comparison group. We included studies that tested the effectiveness of substance use interventions, and measured substance use outcomes, for adults experiencing homelessness in high income countries. Data Collection and Analysis: Descriptive characteristics and statistical information in included studies were coded and checked by at least two members of the review team. Studies selected for the review were assessed for confidence in the findings. Standardised effect sizes were calculated and, if a study did not provide sufficient raw data for the calculation of an effect size, author(s) were contacted to obtain these data. We used random-effects meta-analysis and robust-variance estimation procedures to synthesise effect sizes. If a study included multiple effects, we carried out a critical assessment to determine (even if only theoretically) whether the effects are likely to be dependent. Where dependent effects were identified, we used robust variance estimation to determine whether we can account for these. Where effect sizes were converted from a binary to continuous measure (or vice versa), we undertook a sensitivity analysis by running an additional analysis with these studies omitted. We also assessed the sensitivity of results to inclusion of non-randomised studies and studies classified as low confidence in findings. All included an assessment of statistical heterogeneity. Finally, we undertook analysis to assess whether publication bias was likely to be a factor in our findings. For those studies that we were unable to include in meta-analysis, we have provided a narrative synthesis of the study and its findings. Main Results: We included 48 individual papers covering 34 unique studies. The studies covered 15, 255 participants, with all but one of the studies being from the United States and Canada. Most papers were rated as low confidence (n = 25, or 52%). By far the most common reason for studies being rated as low confidence was high rates of attrition and/or differential attrition of study participants, that fell below the What Works Clearinghouse liberal attrition standard. Eleven of the included studies were rated as medium confidence and 12 studies as high confidence. The interventions included in our analysis were more effective in reducing substance use than treatment as usual, with an overall effect size of -0.11 SD (95% confidence interval [CI], -0.27, 0.05). There was substantial heterogeneity across studies, and the results were sensitive to the removal of low confidence studies (-0.21 SD, 95% CI [-0.59, 0.17] - 6 studies, 17 effect sizes), the removal of quasi-experimental studies (-0.14 SD, 95% CI [-0.30, 0.02] - 14 studies, 41 effect sizes) and the removal of studies where an effect size had been converted from a binary to a continuous outcome (-0.08 SD, 95% CI [-0.31, 0.15] - 10 studies, 31 effect sizes). This suggests that the findings are sensitive to the inclusion of lower quality studies, although unusually the average effect increases when we removed low confidence studies. The average effect for abstinence-based interventions compared to treatment-as-usual (TAU) service provision was -0.28 SD (95% CI, -0.65, 0.09) (6 studies, 15 effect sizes), and for harm reduction interventions compared to a TAU service provision is close to 0 at 0.03 SD (95% CI, -0.08, 0.14) (9 studies, 30 effect sizes). The confidence intervals for both estimates are wide and crossing zero. For both, the comparison groups are primarily abstinence-based, with the exception of two studies where the comparison group condition was unclear. We found that both Assertative Community Treatment and Intensive Case Management were no better than treatment as usual, with average effect on substance use of 0.03 SD, 95% CI [-0.07, 0.13] and -0.47 SD, 95% CI [-0.72, -0.21] 0.05 SD, 95% CI [-0.28, 0.39] respectively. These findings are consistent with wider research, and it is important to note that we only examined the effect on substance use outcomes (these interventions can be effective in terms of other outcomes). We found that CM interventions can be effective in reducing substance use compared to treatment as usual, with an average effect of -0.47 SD, 95% CI (-0.72, -0.21). All of these results need to be considered in light of the quality of the underlying evidence. There were six further interventions where we undertook narrative synthesis. These syntheses suggest that Group Work, Harm Reduction Psychotherapy, and Therapeutic Communities are effective in reducing substance use, with mixed results found for Motivational Interviewing and Talking Therapies (including Cognitive Behavioural Therapy). The narrative synthesis suggested that Residential Rehabilitation was no better than treatment as usual in terms of reducing substance use for our population of interest. Authors' Conclusions: Although our analysis of harm reduction versus treatment as usual, abstinence versus treatment as usual, and harm reduction versus abstinence suggests that these different approaches make little real difference to the outcomes achieved in comparison to treatment as usual. The findings suggest that some individual interventions are more effective than others. The overall low quality of the primary studies suggests that further primary impact research could be beneficial.