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.

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.

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.

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.

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.

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.

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.

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.

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.

The Tradeoffs Between Persistence and Mutation Rates at Sub-Inhibitory Antibiotic Concentrations in Staphylococcus aureus.

The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations not only alters the dynamics of bacterial growth but also increases the mutation rate to antibiotic resistance and decreases the rate of production of persister cells thereby reducing the persistence level. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.

The relationship between type, timing and duration of exposure to adverse childhood experiences and adolescent self-harm and depression: findings from three UK prospective population-based cohorts.

BACKGROUND: Adverse childhood experiences (ACEs) are well-established risk factors for self-harm and depression. However, despite their high comorbidity, there has been little focus on the impact of developmental timing and the duration of exposure to ACEs on co-occurring self-harm and depression. METHODS: Data were utilised from over 22,000 children and adolescents participating in three UK cohorts, followed up longitudinally for 14-18 years: the Avon Longitudinal Study of Parents and Children (ALSPAC), the Millennium Cohort Study (MCS) and the Environmental Risk (E-Risk) Longitudinal Twin Study. Multinomial logistic regression models estimated associations between each ACE type and a four-category outcome: no self-harm or depression, self-harm alone, depression alone and self-harm with co-occurring depression. A structured life course modelling approach was used to examine whether the accumulation (duration) of exposure to each ACE, or a critical period (timing of ACEs) had the strongest effects on self-harm and depression in adolescence. RESULTS: The majority of ACEs were associated with co-occurring self-harm and depression, with consistent findings across cohorts. The importance of timing and duration of ACEs differed across ACEs and across cohorts. For parental mental health problems, longer duration of exposure was strongly associated with co-occurring self-harm and depression in both ALSPAC (adjusted OR: 1.18, 95% CI: 1.10-1.25) and MCS (1.18, 1.11-1.26) cohorts. For other ACEs in ALSPAC, exposure in middle childhood was most strongly associated with co-occurring self-harm and depression, and ACE occurrence in early childhood and adolescence was more important in the MCS. CONCLUSIONS: Efforts to mitigate the impact of ACEs should start in early life with continued support throughout childhood, to prevent long-term exposure to ACEs contributing to risk of self-harm and depression in adolescence.

Sunitinib malate induces cell death in adult human cardiac progenitor cells.

Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 µM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.

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.

Neural correlates of chocolate brand preference: A functional MRI study.

BACKGROUND AND PURPOSE: Preferences can be developed for, or against, specific brands and services. Using two functional magnetic resonance imaging (fMRI) experiments, this study investigated two dissociable aspects of reward processing, craving and liking, in chocolate lovers. The goal was to further delineate the neural basis supporting branding effects using familiar chocolate (FC) and unfamiliar chocolate (UC) brand images. METHODS: In the first experiment, subjects rated their subjective craving and liking on a scale of 1-5 (weak-strong) for each FC and UC image. In the second experiment, they performed a choice task between FC and UC images. RESULTS: Both the craving and liking ratings were significantly greater for FC and were differentially correlated with choice behavior. Craving ratings predicted greater preference for UC, and liking ratings predicted greater preference for FC. A contrast of neural activity for UC versus FC choice trials revealed significantly greater activation for UC choices in the bilateral inferior frontal gyrus and right caudate head. Response times for the FC images were faster than UC images; fMRI activity in the ventromedial prefrontal cortex was significantly correlated with response times during FC trials, but not UC trials. These correlations were significantly different from each other at the group level. CONCLUSIONS: The choices for branded chocolate products are driven by higher subjective reward ratings and lower neural processing demands.

Theoretical considerations and empirical predictions of the pharmaco- and population dynamics of heteroresistance.

Antibiotics are considered one of the most important contributions to clinical medicine in the last century. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulation models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend that the definition of heteroresistance should include a consideration of the rate of return to susceptibility.

Diode laser as an adjunctive treatment for periodontitis: Arandomized controlled trial.

OBJECTIVE: The aim of this randomized controlled trial was to assess clinical and patient reported outcomes of subgingival instrumentation (SI) with adjunctive use of diode laser (DL) versus SI alone in the treatment of periodontitis. METHODS: Participants requiring non-surgical periodontal treatment were randomly allocated into two treatment groups: SI with DL or SI alone. Clinical parameters [full mouth bleeding and plaque scores (FMBS and FMPS), probing pocket depth and clinical attachment level] were recorded at baseline, three and 6 months post-treatment. Visual analogue scale was used to evaluate postoperative participants' perception of pain, swelling, bleeding, bruising and root sensitivity. The impact of periodontal treatment on quality of life was assessed using the General Oral Health Assessment Index (GOHAI) at 6 months. RESULTS: A total of 22 participants with stage III/IV periodontitis completed the 6-month follow-up. SI with or without DL resulted in statistically significant reduction in FMBS, FMPS, PPDs, and percentage of PPDs of ≥5 mm at 3- and 6-month follow-up visits (p = 0.001 to <0.001). The participants in SI/DL group had a greater reduction in the percentage of deep PPDs (≥5 mm) compared to those receiving SI alone, but statistically significant differences between the two groups were not observed (16.40 ± 9.57 vs. 32.50 ± 38.76 at 3 months and 7.20 ± 6.86 vs. 19.50 ± 35.06 at 6 months). The difference in the mean total GOHAI scores was not statistically significant at 6 months with total GOHAI scores of 7.25 ± 2.45 and 5.40 ± 3.06 for SI and SI/DL groups, respectively. CONCLUSION: Within the limitations of this study, the use of DL as an adjunct to SI in the treatment of stage III/IV periodontitis did not produce significant additional improvement in clinical parameters or patient reported outcomes in the 6-month observation period.

How well do parents identify their child's baby teeth? Engagement and accuracy of parent-reported information on a tooth checklist survey.

OBJECTIVES: Naturally exfoliated primary teeth are being increasingly collected in child development studies. Most of these odontological collections and tooth biobanks use parent-reported information from questionnaires or tooth checklists to collect data on offspring teeth. To the best of the authors' knowledge, no studies have assessed parental engagement in tooth checklists, nor parental accuracy in identifying their child's baby tooth. This study aimed to evaluate these dimensions by analysing data from the about this tooth checklist returned with donated primary teeth in a natural experimental study called STRONG (the Stories Teeth Record of Newborn Growth). METHODS: Parental self-reported information were analysed on checklists returned with 825 primary teeth belonging to 199 children. The percentage of blank answers was calculated for each question. The accuracy of parents-reported tooth identification was evaluated by comparing parental ratings to researchers' ratings. Reliability of researchers' tooth identification was first evaluated by calculating intra-observer and inter-observer agreements, as well as Cohen's Kappa values. The percentage of accuracy of parents' tooth identification (relative to researcher's) was then calculated, and logistic regressions were used to evaluate if time elapsed between when exfoliation occurred and the checklist was completed associated with parental accuracy in tooth identification. RESULTS: Parents returned 98.4% of the checklists and completed 74.9% to 97.7% of the questions. Excellent reliability was demonstrated for researchers' intra- and inter-rater tooth identification (agreement percentages >90%; Cohen's Kappa values >.83). Moderate accuracy of parents-reported tooth identifications was found, with parents correctly identifying 49.5% of the donated tooth. Better parental accuracies were highlighted for partial identifications (87.1% of correct jaw, 75.6% of correct tooth type, and 65.8% of correct lateralization). Logistic regressions showed the odds of correct parental identifications decreased on average by 1.8% every 30 days of distance between tooth exfoliation and checklist completion. CONCLUSIONS: While parental engagement is high, parents-reported tooth identifications have moderate accuracy, which decreases over time. High accuracy is however found for partial identifications. Parent-reported information on the accompanying questionnaire of naturally exfoliated primary teeth collection or tooth biobanks, even when filled in a long time after exfoliation took place, should be encouraged. However, expert identifications of teeth should remain best practice.

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.