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The collection, cryopreservation, thawing, and culture of peripheral blood mononuclear cells (PBMCs) can profoundly influence T cell viability and immunogenicity. Gold-standard PBMC processing protocols have been developed by the Office of HIV/AIDS Network Coordination (HANC); however, these protocols are not universally observed. Herein, we have explored the current literature assessing how technical variation during PBMC processing can influence cellular viability and T cell immunogenicity, noting inconsistent findings between many of these studies. Amid the mounting concerns over scientific replicability, there is growing acknowledgement that improved methodological rigour and transparent reporting is required to facilitate independent reproducibility. This review highlights that in human T cell studies, this entails adopting stringent standardised operating procedures (SOPs) for PBMC processing. We specifically propose the use of HANC's Cross-Network PBMC Processing SOP, when collecting and cryopreserving PBMCs, and the HANC member network International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) PBMC Thawing SOP when thawing PBMCs. These stringent and detailed protocols include comprehensive reporting procedures to document unavoidable technical variations, such as delayed processing times. Additionally, we make further standardisation and reporting recommendations to minimise and document variability during this critical experimental period. This review provides a detailed overview of the challenges inherent to a procedure often considered routine, highlighting the importance of carefully considering each aspect of SOPs for PBMC collection, cryopreservation, thawing, and culture to ensure accurate interpretation and comparison between studies. [ABSTRACT FROM AUTHOR]

Specialized cancer treatments have the potential to exploit glutamine dependence to increase patient survival rates. Glutamine diagnostics capable of tracking a patient's response to treatment would enable a personalized treatment dosage to optimize the tradeoff between treatment success and dangerous side effects. Current clinical glutamine testing requires sophisticated and expensive lab-based tests, which are not broadly available on a frequent, individualized basis. To address the need for a low-cost, portable glutamine diagnostic, this work engineers a cell-free glutamine biosensor to overcome assay background and signal-to-noise limitations evident in previously reported studies. The findings from this work culminate in the development of a shelf-stable, paper-based, colorimetric glutamine test with a high signal strength and a high signal-to-background ratio for dramatically improved signal resolution. While the engineered glutamine test is important progress towards improving the management of cancer and other health conditions, this work also expands the assay development field of the promising cell-free biosensing platform, which can facilitate the low-cost detection of a broad variety of target molecules with high clinical value. [ABSTRACT FROM AUTHOR]

In 1938, the first distal femur of a fossil Australopithecus was discovered at Sterkfontein, South Africa. A decade later, another distal femur was discovered at the same locality. These two fossil femora were the subject of a foundational paper authored by Kingsbury Heiple and Owen Lovejoy in 1971. In this paper, the authors discussed functionally relevant anatomies of these two fossil femora and noted their strong affinity to the modern human condition. Here, we update this work by including eight more fossil Australopithecus distal femora, an expanded comparative dataset, as well as additional linear measurements. Just as Heiple and Lovejoy reported a half‐century ago, we find strong overlap between modern humans and cercopithecoids, except for inferiorly flattened condyles and a high bicondylar angle, both of which characterize modern humans and Australopithecus and are directly related to striding bipedalism. All other measured aspects of the femora are by‐products of these key morphological traits. Additional fossil material from the early Pliocene will help to inform the evolution of the hominin distal femur and its condition in the Pan‐Homo common ancestor that preceded bipedal locomotion. [ABSTRACT FROM AUTHOR]

The poor quality of life associated with the loss of teeth can be improved by the placing of dental implants. However, successful implantation relies on integration with soft tissues or peri-implant inflammatory disease that can lead to the loss of the implant. Pharmacological agents, such as antibiotics and antiseptics, can be used as adjunct therapies to facilitate osseointegration; however, they can have a detrimental effect on cells, and resistance is an issue. Alternative treatments are needed. Hence, this study aimed to examine the safety profile of bergenin (at 2.5 μM and 5 μM), a traditional medicine, towards human gingival fibroblasts cultured on acid-etched zirconia implant surfaces. Cellular responses were analysed using SEM, resazurin assay, and scratch wound healing assay. Qualitative assessment was conducted for morphology (day 1) and attachment (early and delayed), and quantitative evaluation for proliferation (day 1, 3, 5 and 7), and migration (0 h, 6 h and 24 h). The concentrations of bergenin at 2.5 μM and 5 μM did not demonstrate a statistically significant effect with regard to any of the cellular responses (p > 0.05) tested. In conclusion, bergenin is non-cytotoxic and is potentially safe to be used as a local pharmacological agent for the management of peri-implant inflammatory diseases. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effects of bisphosphonates, namely, alendronate and zoledronate, on the osteogenic activity of osteoprogenitor cells cultured on titanium surfaces at therapeutic doses in order to assess if altered osteoblastogenesis could compromise osseointegration and contribute to etiopathogenesis of painful disorders such as bisphosphonates-related osteonecrosis of the jaw (BRONJ) following implant placement. Materials and Methods: MC3T3-E1 Subclone 4 cells were utilized in this study. Therapeutic doses of alendronate and zoledronate were calculated based on reported peak plasma concentrations. The viability, proliferation, adhesion, and mineralization potential of cells was assessed using a LIVE/DEAD stain, alamarBlue assay, immunofluorescence microscopy, and Alizarin Red S staining, respectively. Results: Therapeutic doses of zoledronate negatively affected cell viability, whereas therapeutic doses of alendronate significantly enhanced cell differentiation and the amount of bone formation compared with the control. Conclusion: The findings of this study may provide some insight into the pathogenesis of BRONJ development following implant placement in patients treated with zoledronate and may have promising implications toward improved wound healing and osseointegration in patients treated with alendronate. [ABSTRACT FROM AUTHOR]

Purpose: An identification card facilitates access to municipal services for migrants with precarious status (MPS) in Montreal. The purpose of this study was to explore from MPS' perspective the utility of the identity (ID) card and its influence on social inclusion for MPS. Design/methodology/approach: A sequential explanatory mixed methods design was used. First, a descriptive phone survey was administered (n = 119). Associations between ID card use and levels of social inclusion were assessed using ordinal logistic regression. Second, semi-structured interviews (n = 12) were done with purposely selected participants. Results were mixed using a statistics-by-theme approach. Findings: Results showed that ID card users compared to nonusers reported higher levels of participation in society and more control/independence in daily life. No statistical associations were found between card use and sense of belonging nor sense of safety. Interviews highlighted that the ID card enabled participation in socio-recreational activities and perceived empowerment. A heightened sense of belonging was also found. Interview participants expressed fear of police despite owning the ID card. Practical implications: Overall, although the municipal ID card promoted social inclusion for MPS, there is a need to render the ID card official to fully achieve this goal. Findings can inform the creation of public policies that foster inclusion and health of MPS in cities around the world. Originality/value: Evaluation from MPS' perspectives of the first ID card program of its kind in Canada. [ABSTRACT FROM AUTHOR]

Mpox is a new public health outbreak that particularly threatens the homeless population. Street Medicine Phoenix (SMP) is a student-led interprofessional volunteer organization that provides medical care and other essential services to individuals experiencing homelessness in Phoenix, Arizona. In addition to core services such as wound care; health screenings (blood pressure and blood glucose.); vision screenings; HIV testing; naloxone education and distribution; flu, COVID-19, and Hepatitis A vaccinations; and community resource referrals, SMP began offering mpox education and vaccination at outreach events. During an outreach event shortly after the onset of the mpox outbreak, SMP identified 2 suspected mpox cases. Accordingly, SMP has partnered with the Maricopa County Public Health Department to set up mobile mpox vaccination clinics on the streets outside of Phoenix Arizona's largest homeless shelter. We share the details of these 2 cases along with our early efforts vaccinating individuals experiencing homelessness for mpox via our mobile vaccination clinic. Our experiences demonstrate the importance of community agencies providing direct outreach to underserved populations where they are at, particularly the homeless population, to address public health concerns such as emerging disease outbreaks like mpox. In addition, these cases highlight the potential significant impact that street medicine programs can have on their respective homeless communities in the context of infectious disease mitigation and emphasize the importance of partnerships with local health departments. [ABSTRACT FROM AUTHOR]

Background: This study assesses the impact of the Interprofessional Global Health Course (IPGHC) on students' fundamental global health knowledge and personal viewpoints on global health domains. It explores the evolution of students' understanding of global health specifically in relation to the COVID-19 pandemic. Methods: Ninety-nine students were selected from 123 McGill student applicants based on their motivation and commitment to take part in IPGHC's ten-week 2020 curriculum. These IPGHC students were eligible to participate in the study. The study's design is sequential explanatory mixed methods. The cross-sectional survey (quantitative phase) appraises students' global health learning outcomes using pre- and post-course surveys, with the use of 5-point Likert-scale questions. The descriptive qualitative survey (qualitative phase) further explores the impact of IPGHC on student's understanding of global health and the reflections of students on the COVID-19 pandemic after IPGHC. The post-course survey included a course evaluation for quality improvement purposes. Results: Of the 99 students, 81 students across multiple undergraduate and graduate disciplines participated in the study by completing the course surveys. Mean knowledge scores of the following 11 global health topics were increased between pre- and post-course survey: Canadian Indigenous health (P < 0.001), global burden of disease (P < 0.001), global surgery (P < 0.001), infectious diseases and neglected tropical diseases (P < 0.001), refugee and immigrant health (P < 0.001), research and development of drugs (P < 0.001), role of politics and policies in global health (P = 0.02), role of technology in global health (P < 0.001), sexual violence (P < 0.001), systemic racism in healthcare (P = 0.03), and trauma in the global health context (P < 0.001). A positive change in student viewpoints was observed in response to questions regarding their perception of the importance of global health education in their own professional health care programs (P < 0.001), and their understanding of the roles and responsibilities of other healthcare professionals (P < 0.001). In the post-course survey open-ended questions, students exemplified their knowledge gained during the course to create a more informed definition of global health. Several recurring themes were identified in the student reflections on the COVID-19 pandemic, notably policy and politics, followed by access to healthcare and resources. Conclusion: This study emphasizes the need for interprofessional global health education at the university level and demonstrates how rapidly global health learners can apply their knowledge to evolving contexts like the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

In 2011, the political events of the "Arab Spring" that spread in almost all Arab countries shed light on what were perceived as new actors, new forms, and new voices of youth political expression. Among the new actors, groups of football fans, known as Ultras, came to the forefront. The sociolinguistic aspects of their cultural productions have so far attracted little academic attention apart from a few papers dealing with emblematic songs that recently became popular protest chants. This paper aims at investigating a few characteristic linguistic features present in numerous Moroccan Ultras songs, such as language mixing and affrication, and comparing them with more general youth language practices. Do Ultras' performances contribute to the generalization of certain youth traits as well as to the diffusion of a more global aesthetic and masculine ethos? The emotional aspect of the Ultras' culture makes them "natural" candidates for expressing the people's discontent, thus pointing to similarities between political slogans and Ultras songs. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the effects of celecoxib and ibuprofen on the proliferation, viability, and migration of MC3T3-E1 cells cultured on titanium surfaces. Materials and Methods: MC3T3-E1 cells were cultured on sandblasted titanium disks and allocated to one of the following six groups: (a) control (untreated); (b) celecoxib (5 µM and 10 µM); (c) ibuprofen (5 µM and 10 µM); and (d) prostaglandin E2 (10 µM). Proliferation of attached cells was assessed over 9 days using an alamarBlue assay. A trypan blue exclusion test was conducted to assess cell viability; the relative percentages of live and dead cells were quantified using a hemocytometer over 2 days. A Boyden-Chamber Assay was utilized to assess cell migration over 3 days. Results: The proliferation of cells treated with any intervention was not significantly different than that of the untreated group throughout the treatment period. However, celecoxib and ibuprofen significantly decreased the percentage of viable cells in a dose-dependent manner. Specifically, celecoxib (10 µM) and ibuprofen (5 µM and 10 µM, respectively) on day 1 and celecoxib (10 µM) on day 2 showed significantly higher percentages of dead cells compared to the untreated cells. There was a significant increase in migration of cells treated with ibuprofen (5 µM) compared to untreated cells on day 1; however, the migration of cells treated with any of the interventions was not significantly different from that of untreated cells on day 3. Conclusion: Nonsteroidal anti-inflammatory drugs at therapeutic doses did not significantly affect osteoblast proliferation and migration. However, higher dosages of celecoxib (10 µM) significantly reduced the cell viability and therefore can potentially affect the process of osseointegration. [ABSTRACT FROM AUTHOR]

Family-Based Treatment (FBT)—the most widely supported treatment for pediatric eating disorders—transitioned to virtual delivery in many programs due to COVID-19. Using a blended implementation approach, we systematically examined therapist adherence to key components of FBT and fidelity to FBT by videoconferencing (FBT-V), preliminary patient outcomes, and team experiences with our FBT-V implementation approach as well as familial perceptions of FBT-V effectiveness. We examined our implementation approach across four pediatric eating disorder programs in Ontario, Canada, using mixed methods. Participants included therapists (n = 8), medical practitioners (n = 4), administrators (n = 6), and families (n = 5; 21 family members in total). We developed implementation teams at each site, provided FBT-V training, and offered clinical and implementation consultation. Therapists submitted video recordings of their first four FBT-V sessions for fidelity rating, and patient outcomes. Therapists self-reported readiness, attitudes, confidence, and adherence to FBT-V. Focus groups were conducted with each team and family after the first four sessions of FBT-V. Quantitative data were analyzed using repeated measures ANOVA. Qualitative data were analyzed using directed and summative content analysis. Therapists adhered to key FBT components and maintained FBT-V fidelity. Changes in therapists' readiness, attitudes, and confidence in FBT-V over time were not significant. All patients gained weight. Focus groups revealed implementation facilitators/barriers, positives/negatives surrounding FBT-V training and consultation, suggestions for improvement, and effectiveness attributed to FBT-V. Our implementation approach appeared to be feasible and acceptable. Future research with a larger sample is required, furthering our understanding of this approach and exploring how organizational factors influence treatment fidelity. [ABSTRACT FROM AUTHOR]

Objective: Though virtual outpatient psychotherapy for eating disorders is likely effective, less is known about virtual higher levels of care. The current study examined the clinical outcomes of a family‐based virtual intensive outpatient program (vIOP) for youth with eating disorders which was developed in response to the COVID‐19 pandemic, compared to the same institution's in‐person partial hospital program (PHP). Methods: Treatment outcomes were assessed via chart review in 102 patients between the ages of 9–23 (M = 15.2, SD = 2.5) who were predominantly cisgender female (84.3%) and primarily diagnosed with anorexia nervosa (64.7%) or atypical anorexia (23.5%). Participants were either treated in the in‐person PHP before the pandemic (n = 49) or the vIOP during the pandemic (n = 53). Percent expected body weight (%EBW) was examined at baseline, end of treatment, 3‐months post‐treatment, and 6‐months post‐treatment, as well as the frequency of medical, psychiatric, and residential admissions before, during, and after vIOP or PHP participation. Results: Linear mixed models demonstrated no effect of treatment modality (in‐person versus virtual) on %EBW over time. The duration of the vIOP was, on average, 12 calendar days longer, though the amount billed for the vIOP was lower. Survival analyses and Cox regression models did not suggest differences in the frequency of hospital and residential treatment admissions during treatment (vIOP: 9.4%, PHP: 10.0%) or post‐treatment (vIOP: 15.0%, PHP: 10.2%). Discussion: Findings support virtual family‐based programs as suitable alternatives to in‐person treatment and underscore the potential cost‐effectiveness of a family‐based IOP versus PHP. Public Significance: This study demonstrates that a virtual, family‐based, intensive outpatient program for youth with eating disorders had similar treatment outcomes to an in‐person partial hospitalization program. Specifically, the virtual and in‐person programs had similar weight restoration outcomes and rates of medical, psychiatric, or residential treatment admissions during or after treatment initiation. Findings support the use of virtual treatment, even for youth requiring a high level of intervention. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Epidermolysis bullosa (EB) causes blistering and scarring of the hands resulting in contractures fused web spaces and altered function. Surgery is needed to release contractures and web spaces and hand therapy is essential to maintain results, approaches for both differ. WHAT DOES THIS STUDY ADD?: These guidelines aim to provide information on the surgical and conservative therapeutic hand management of children and adults diagnosed with EB. They are based on available evidence and expert consensus to assist hand surgeons and therapists in decision making, planning and treatment. They highlight the importance of a holistic multidisciplinary team (MDT) approach, where patient priorities are paramount. [ABSTRACT FROM AUTHOR]

Background and objectives: Dimethyl fumarate (DMF), an oral disease-modifying therapy with an established benefit and well-described safety profile, is among the most commonly used therapies for relapsing forms of multiple sclerosis. As of 31 December 2021, >560,000 patients have been treated with DMF, representing >1,190,000 person-years of exposure. Of these, 6413 patients (14,292 person-years) were from clinical trials. Methods and results: Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of lymphopenia (<0.91 × 109/L) in patients treated with DMF. We present detailed clinical characteristics and outcomes of the 12 confirmed PML cases occurring in MS patients on DMF as of 21 July 2021. The PML incidence in DMF-treated patients is 1.07 per 100,000 person-years of DMF exposure. Lymphopenia is the common risk for PML in DMF treatment. Discussion: DMF-related PML is rare but has occurred in the setting of lymphopenia, supporting the current recommendations for absolute lymphocyte count monitoring in all patients, regardless of age and time on therapy. [ABSTRACT FROM AUTHOR]

COVID-19, the global pandemic, has significantly interrupted the provision of oral health care to many individuals. This study aims to evaluate patients' attitudes to and perceptions of dental visits in the COVID-19 pandemic and assess if socio-economic status influences their perception of risk associated with dental visits. Patients attending the dental clinic were invited to participate in this study by completing a questionnaire administered in August 2021. Composite indicators for access, attitude, perception and socio-economic status were created based on subsets of questions. A total of 247 completed questionnaires were obtained. Analysis was performed with the perception, attitude and access indicators against the socio-economic status indicator. This study found that there is a statistically significant difference between socio-economic groups and their attitudes and perceptions around dental health care services in the current COVID-19 pandemic. Individuals from lower socio-economic status groups were less influenced by the pandemic. Participants from higher socio-economic status groups were found to be more cautious around COVID-19 and its risks. [ABSTRACT FROM AUTHOR]

Preterm infants suffer from a higher incidence of acute diseases such as necrotising enterocolitis and sepsis. This risk can be mitigated through probiotic prophylaxis during admission. This reduction in risk is likely the result of acute modulation of the gut microbiome induced by probiotic species, which has been observed to occur up until discharge. We aimed to determine if this modulation, and the associated probiotic species, persisted beyond discharge. We conducted both a cross-sectional analysis (n = 18), at ~ 18 months of age, and a longitudinal analysis (n = 6), from admission to 18 months of the gut microbiome of preterm infants using both shotgun metagenomics and 16S rRNA profiling respectively. The 16S amplicon sequencing revealed that the microbial composition of the probiotic-supplemented infants changed dramatically over time, stabilising at discharge. However, species from the probiotic Infloran®, as well as positive modulatory effects previously associated with supplementation, do not appear to persist beyond discharge and once prophylaxis has stopped.    Conclusions: Although differences exist between supplemented and non-supplemented groups, the implications of these differences remain unclear. Additionally, despite a lack of long-term colonisation, the presence of probiotics during early neonatal life may still have modulatory effects on the microbiome assembly and immune system training. What is Known: • Evidence suggests modulation of the microbiome occurs during probiotic prophylaxis, which may support key taxa that exert positive immunological benefits. • Some evidence suggests that this modulation can persist post-prophylaxis. What is New: • We present support for long-term modulation in association with probiotic prophylaxis in a cohort of infants from North Queensland Australia. • We also observed limited persistence of the probiotic species post-discharge. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, outpatient eating disorder care, including Family-Based Treatment (FBT), rapidly transitioned from in-person to virtual delivery in many programs. This paper reports on the experiences of teams and families with FBT delivered by videoconferencing (FBT-V) who were part of a larger implementation study. Methods: Four pediatric eating disorder programs in Ontario, Canada, including their therapists (n = 8), medical practitioners (n = 4), administrators (n = 6), and families (n = 5), participated in our study. We provided FBT-V training and delivered clinical consultation. Therapists recorded and submitted their first four FBT-V sessions. Focus groups were conducted with teams and families at each site after the first four FBT-V sessions. Focus group transcripts were transcribed verbatim and key concepts were identified through line-by-line reading and categorizing of the text. All transcripts were double-coded. Focus group data were analyzed using directed and summative qualitative content analysis. Results: Analysis of focus group data from teams and families revealed four overarching categories—pros of FBT-V, cons of FBT-V, FBT-V process, and suggestions for enhancing and improving FBT-V. Pros included being able to treat more patients and developing a better understanding of family dynamics by being virtually invited into the family's home (identified by teams), as well as convenience and comfort (identified by families). Both teams and families recognized technical difficulties as a potential con of FBT-V, yet teams also commented on distractions in family homes as a con, while families expressed difficulties in developing therapeutic rapport. Regarding FBT-V process, teams and families discussed the importance and challenge of patient weighing at home. In terms of suggestions for improvement, teams proposed assessing a family's suitability or motivation for FBT-V to ensure it would be appropriate, while families strongly suggested implementing hybrid models of FBT in the future which would include some in-person and some virtual sessions. Conclusion: Team and family perceptions of FBT-V were generally positive, indicating acceptability and feasibility of this treatment. Suggestions for improved FBT-V practices were made by both groups, and require future investigation, such as examining hybrid models of FBT that involve in-person and virtual elements. Trial registration ClinicalTrials.gov NCT04678843. Plain English summary: Family-Based Treatment—the leading outpatient treatment for children and adolescents with eating disorders—rapidly transitioned to virtual delivery during the COVID-19 pandemic in many programs. This study qualitatively describes the perceptions and experiences of teams and families related to the first four sessions of Family-Based Treatment delivered via videoconferencing (FBT-V) during the COVID-19 pandemic, using end-of-study focus groups. Our findings suggest that FBT-V is generally well-received amongst these stakeholders. Therapists found that implementing FBT-V was relatively seamless, and families described the convenience and comfort of sessions taking place virtually in their own homes. However, therapists revealed concerns of distractions in family homes impacting sessions, and families had some difficulties in developing therapeutic rapport. As a result, additional modes of delivering Family-Based Treatment should be explored to address challenges present in virtual care. This might include hybrid models of treatment delivery, involving a combination of in-person and virtual sessions. [ABSTRACT FROM AUTHOR]

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment. [ABSTRACT FROM AUTHOR]

Objective: In the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center. Methods: MRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48–96. Results: Across studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0–48, mean ± SE percentage change in BPF was −0.44 ± 0.04 vs. −0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48–96, mean ± SE percentage change in BPF was −0.27 ± 0.03 vs. −0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48–96, estimated change (95% confidence interval) in BPF was −0.0021 (−0.0027, −0.0016) for DMF vs. −0.0033 (−0.0039, −0.0028) for PBO (35.9% reduction; p = 0.0025). Conclusions: The lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of routinely used physical decontamination methods on the surface characteristics of zirconia implants and subsequent ability of bacteria to adhere in vitro. Background: Physical decontamination methods commonly used in peri‐implantitis therapy and routine implant maintenance can potentially alter zirconia implant surfaces. Methods: Acid‐etched zirconia discs were instrumented with titanium curette (TC), plastic curette, air abrasive device, ultrasonic scaler (US) with stainless steel tip. Following instrumentation, surface topography, and surface elemental composition was analyzed using 3D‐laser scanning microscopy and energy‐dispersive X‐ray spectroscopy, respectively. Subsequently, plaque biofilm was cultured on zirconia discs for 48 h and bacterial adhesion assessed using a turbidity test and scanning electron microscopy. Results: A significant difference in surface roughness was observed between the US and control group (p < 0.05). The US and TC caused gray surface discolouration on zirconia discs due to deposition of metallic residue as confirmed by X‐ray spectroscopy. No significant difference in bacterial adhesion was noted among all treatment groups (p > 0.05). Conclusion: TC and US with stainless steel tips should be used with caution due to deposition of metallic residue on the surface. Air abrasive devices and plastic curettes caused minimal surface alterations and are, therefore, safer for zirconia implant decontamination. [ABSTRACT FROM AUTHOR]

Background: Prior studies suggest comparable effectiveness of dimethyl fumarate (DMF) and fingolimod (FTY) in multiple sclerosis (MS) using relapse, Expanded Disability Status Score (EDSS), and magnetic resonance imaging (MRI) lesion metrics. Objective: Compare the real-world effectiveness of DMF versus FTY using quantitative, validated neuroperformance tests, MRI, and serum neurofilament light chain (sNfL) outcomes while controlling for between-group differences. Methods: Patients were eligible if on DMF or FTY when first enrolled in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network and had ≥1-year follow-up in MS PATHS. Sensitivity analysis included a subgroup who started DMF/FTY ≤2 years from enrolment. After propensity score weighting, differences in means and in mean 1-year change of neuroperformance and MRI outcomes were compared. sNfL levels were assessed. This was a non-randomized comparison. Results: In the overall cohort, no significant differences were observed between DMF (n = 702) and FTY (n = 600) in neuroperformance or MRI outcomes including brain volume loss; mean time (SD) since treatment initiation was 1.98 (0.68) years for DMF and 2.02 (0.75) years for FTY. A sensitivity analysis controlling for DMF and FTY treatment duration yielded similar results. Conclusion: In this study, DMF and FTY demonstrated similar effects on physical and cognitive neuroperformance and MRI outcomes. Direct comparisons to other fumarates and S1P receptor modulators were not conducted. [ABSTRACT FROM AUTHOR]

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Bipedal trackways discovered in 1978 at Laetoli site G, Tanzania and dated to 3.66 million years ago are widely accepted as the oldest unequivocal evidence of obligate bipedalism in the human lineage1–3. Another trackway discovered two years earlier at nearby site A was partially excavated and attributed to a hominin, but curious affinities with bears (ursids) marginalized its importance to the paleoanthropological community, and the location of these footprints fell into obscurity3–5. In 2019, we located, excavated and cleaned the site A trackway, producing a digital archive using 3D photogrammetry and laser scanning. Here we compare the footprints at this site with those of American black bears, chimpanzees and humans, and we show that they resemble those of hominins more than ursids. In fact, the narrow step width corroborates the original interpretation of a small, cross-stepping bipedal hominin. However, the inferred foot proportions, gait parameters and 3D morphologies of footprints at site A are readily distinguished from those at site G, indicating that a minimum of two hominin taxa with different feet and gaits coexisted at Laetoli.Reanalysis of bipedal trackways from Laetoli site A in Tanzania suggest that the footprints were made by a hominin that coexisted with at least one other hominin species. [ABSTRACT FROM AUTHOR]

Ablative fractional laser treatment is considered the gold standard for skin rejuvenation. In order to understand how fractional laser works to rejuvenate skin, we performed microarray profiling on skin biopsies to identify temporal and dose-response changes in gene expression following fractional laser treatment. The backs of 14 women were treated with ablative fractional laser (Fraxel®) and 4 mm punch biopsies were collected from an untreated site and at the treated sites 1, 3, 7, 14, 21 and 28 days after the single treatment. In addition, in order to understand the effect that multiple fractional laser treatments have on skin rejuvenation, several sites were treated sequentially with either 1, 2, 3, or 4 treatments (with 28 days between treatments) followed by the collection of 4 mm punch biopsies. RNA was extracted from the biopsies, analyzed using Affymetrix U219 chips and gene expression was compared between untreated and treated sites. We observed dramatic changes in gene expression as early as 1 day after fractional laser treatment with changes remaining elevated even after 1 month. Analysis of individual genes demonstrated significant and time related changes in inflammatory, epidermal, and dermal genes, with dermal genes linked to extracellular matrix formation changing at later time points following fractional laser treatment. When comparing the age-related changes in skin gene expression to those induced by fractional laser, it was observed that fractional laser treatment reverses many of the changes in the aging gene expression. Finally, multiple fractional laser treatments, which cover different regions of a treatment area, resulted in a sustained or increased dermal remodeling response, with many genes either differentially regulated or continuously upregulated, supporting previous observations that maximal skin rejuvenation requires multiple fractional laser treatments. In conclusion, fractional laser treatment of human skin activates a number of biological processes involved in wound healing and tissue regeneration. [ABSTRACT FROM AUTHOR]

The present systematic review evaluates the safety of placing dental implants in patients with a history of antiresorptive or antiangiogenic drug therapy. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. PubMed, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and OpenGrey databases were used to search for clinical studies (English only) to July 16, 2019. Study quality was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases using a modified Newcastle-Ottawa scale and the Joanna Briggs Institute critical appraisal checklist for case series. A broad search strategy resulted in the identification of 7542 studies. There were 28 studies reporting on bisphosphonates (5 cohort, 6 case control, and 17 case series) and 1 study reporting on denosumab (case series) that met the inclusion criteria and were included in the qualitative synthesis. The quality assessment revealed an overall moderate quality of evidence among the studies. Results demonstrated that patients with a history of bisphosphonate treatment for osteoporosis are not at increased risk of implant failure in terms of osseointegration. However, all patients with a history of bisphosphonate treatment, whether taken orally for osteoporosis or intravenously for malignancy, appear to be at risk of "implant surgery-triggered" medication-related osteonecrosis of the jaw (MRONJ). In contrast, the risk of MRONJ in patients treated with denosumab for osteoporosis was found to be negligible. In conclusion, general and specialist dentists should exercise caution when planning dental implant therapy in patients with a history of bisphosphonate and denosumab drug therapy. Importantly, all patients with a history of bisphosphonates are at risk of MRONJ, necessitating this to be included in the informed consent obtained before implant placement. [ABSTRACT FROM AUTHOR]

Introduction: Persistence to multiple sclerosis (MS) disease-modifying therapy is fundamental for maximal treatment outcomes. Diroximel fumarate (DRF) is approved in the USA for relapsing MS. Following oral administration, DRF is metabolized to monomethyl fumarate, the active metabolite of dimethyl fumarate (DMF). DRF showed clinically significant improvements in gastrointestinal (GI) tolerability versus DMF in a head-to-head clinical trial; however, real-world persistence/adherence has not been assessed. We evaluated persistence/adherence in DRF-treated patients in a real-world clinical practice. Methods: This retrospective analysis of the AcariaHealth Specialty Pharmacy Program included patients initiating DRF from 4 December 2019 through 3 April 2020 and followed until data extraction (31 August 2020). Exclusion criteria included undetermined treatment status (e.g., DRF prescription transfer to a different pharmacy). Endpoints included persistence (overall proportion of patients remaining on DRF), discontinuation rate due to GI adverse events (AEs), and adherence (proportion of days covered [PDC]). GI AEs included GI-related AEs occurring at any time, or any unknown AE without details about the nature of the event if the unknown AE occurred ≤ 90 days after DRF initiation. Results: Overall, 160 patients with MS were included. Median (range) patient age was 51 (20−79) years, 80.6% (129/160) of patients were female, and 16.3% (26/160) had prior DMF treatment. Median (range) treatment duration was 7.6 (0.1−10.4) months. Estimated proportion of patients remaining persistent on DRF treatment at 8 months was 88.6% (95% confidence interval [CI] 82.5–2.7). Overall, 3.8% (6/160) of patients discontinued due to GI AEs. Mean PDC was 91.4% (95% CI 89.1−93.7). In a DMF-to-DRF switch subgroup, 92.3% (24/26) remained persistent on DRF, and 3.8% (1/26) discontinued DRF due to GI AEs. Conclusion: This real-world analysis of DRF-treated patients showed high overall persistence, low discontinuation rate due to GI AEs, and high adherence to therapy, aligning with expectations based on DRF clinical trials. Data were consistent in the DMF-to-DRF subgroup. Infographic: [ABSTRACT FROM AUTHOR]

Background: Delayed-release dimethyl fumarate (DMF) demonstrates sustained efficacy and safety for relapsing forms of MS. Absolute lymphocyte count (ALC) is reduced initially, then stabilizes on treatment. Objective: PROCLAIM, a 96-week, prospective, open-label, phase 3b study, assessed lymphocyte subsets and immunoglobulin (Ig) levels during 48 and 96 weeks (W) of DMF treatment. Methods: Patients received 240 mg DMF BID. Endpoints: lymphocyte subset count changes (primary); Ig isotypes and ALC changes (secondary); adverse events and relationship between ALC changes and ARR/EDSS (exploratory); and neurofilament assessment (ad hoc). Results: Of 218 patients enrolled, 158 (72%) completed the study. Median ALC decreased 39% from baseline to W96 (BL–W96), stabilizing above the lower limit of normal (baseline: 1.82 × 109/L; W48: 1.06 × 109/L; W96: 1.05 × 109/L). CD4 + and CD8 + T cells correlated highly with ALC from BL–W96 (p < 0.001). Relative to total T cells, naive CD4 + and CD8 + T cells increased, whereas CD4 + and CD8 + central and effector memory T cells decreased. Total IgA, IgG, IgM, and IgG1–4 subclass levels remained stable. Adverse event rates were similar across ALC subgroups. ARR, EDSS, and neurofilament were not correlated with ALCs. Conclusion: Lymphocyte decreases with DMF were maintained over treatment, yet immunoglobulins remained stable. No increase in infection incidence was observed in patients with or without lymphopenia. Support: Biogen [ABSTRACT FROM AUTHOR]

Objective: The COVID-19 pandemic has had detrimental effects on mental health. Literature on the impact on individuals with eating disorders is slowly emerging. While outpatient eating disorder services in Canada have attempted to transition to virtual care, guidelines related to optimal virtual care in this field are lacking. As such, the objective of our Canadian Consensus Panel was to develop clinical practice guidelines related to the provision of virtual care for children, adolescents, and emerging adults living with an eating disorder, as well as their caregivers, during the COVID-19 pandemic and beyond. Methods: Using scoping review methodology (with literature in databases from 2000 to 2020 and grey literature from 2010 to 2020), the Grading of Recommendations, Assessment, Development, and Evaluation system, the Appraisal of Guidelines, Research and Evaluation tool, and a panel of diverse stakeholders from across Canada, we developed high quality treatment guidelines that are focused on virtual interventions for children, adolescents, and emerging adults with eating disorders, and their caregivers. Results: Strong recommendations were supported specifically in favour of in-person medical evaluation when necessary for children, adolescents, and emerging adults, and that equity-seeking groups and marginalized youth should be provided equal access to treatment. For children and adolescents, weak recommendations were supported for telehealth family-based treatment (FBT) and online guided parental self-help FBT. For emerging adults, internet cognitive-behavioural therapy (CBT)-based guided self-help was strongly recommended. Weak recommendations for emerging adults included CBT-based group internet interventions as treatment adjuncts, internet-based relapse prevention Maudsley Model of Anorexia Nervosa Treatment for Adults (MANTRA) guided self-help, telehealth relapse prevention using MANTRA, and guided CBT-based smartphone apps as treatment adjuncts. For caregivers of children and adolescents, weak recommendations were supported for virtual parent meal support training, and moderated online caregiver forums and support groups. For caregivers of emerging adults, guided parental self-help CBT was strongly recommended, and unguided caregiver psychoeducation self-help was weakly recommended. Conclusions: Several gaps for future work were identified including the impact of sex, gender, race, and socioeconomic status on virtual care among children, adolescents, and emerging adults with eating disorders, as well as research on more intensive services, such as virtual day hospitals. [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing–remitting MS who received DRF or DMF in EVOLVE-MS-2. Methods: A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work. Results: In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere 'quite a bit' or 'extremely' with regular daily activities [IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2–3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) versus DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF. Conclusions: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use. Trial registration: [ClinicalTrials.gov identifier: NCT03093324] [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing–remitting MS who received DRF or DMF in EVOLVE-MS-2. Methods: A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work. Results: In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere 'quite a bit' or 'extremely' with regular daily activities [IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2–3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) versus DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF. Conclusions: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use. Trial registration: [ClinicalTrials.gov identifier: NCT03093324] [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13–0.20). Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS. [ABSTRACT FROM AUTHOR]

Health profession programs routinely utilize traditional interviews in admissions as a means of assessing important non-academic characteristics (e.g., critical thinking, interpersonal skills, judgment) of candidates. However, the reliability and validity of traditional interviews is highly questionable. Given this, multiple health profession programs (e.g., medicine, nursing, pharmacy, physical therapy) have implemented multiple mini-interviews as an alternative for assessing non-academic characteristics. This paper describes the development and implementation of multiple mini-interviews in the admissions process for a doctoral clinical psychology program, one of the health professions yet to use multiple mini-interviews. This paper also examines the feasibility and acceptability of the multiple mini-interviews in this program. Results of a mixed-method survey of all 120 candidates who participated in admissions days are presented along with discussion of factors associated with satisfaction and dissatisfaction. Recommendations for program refinement and application to other graduate psychology programs for improved admissions processes are discussed. [ABSTRACT FROM AUTHOR]

The main emphasis of this paper is on the use of Retarding Potential Analyzers (RPAs) for measuring the electron and ion distribution functions, density, and temperature of space plasmas and the charging level of spacecraft surfaces interacting with the plasmas. Multiple grids of progressively negative potential are used to suppress the secondary electrons produced at the entrance of an RPA. We point out that it is impossible to achieve complete suppression. The secondary electrons collected by the receiver may produce a spurious lump in the distribution measured. Improved designs and space applications for spacecraft charging and ionic liquid ion beam diagnostics are discussed. Spacecraft charging will be very important for planetary explorations, whereas ionic liquid ion beams will be important for spacecraft propulsion in the future. [ABSTRACT FROM AUTHOR]

Purpose: This study compared performance on the Syllable Repetition Task (SRT) by preschoolers with diverse speech and language abilities to identify underlying impairments in speech processes. Method: Three groups of 13 children ages 4 and 5 years with (a) typically developing (TD) speech and language, (b) speech sound disorder (SSD), and (c) comorbid developmental language disorder and speech sound disorder (DLD + SSD) completed the SRT. We calculated competence, memory, encoding, and transcoding scores, as well as word-initial stress pattern and vowel accuracy. Results: A 3 × 3 (Group × Syllable length) factorial multivariate analysis of covariance revealed group differences for all measures and syllable length differences for memory, transcoding, and competence. There were no interactions between group and syllable length. TD children obtained the highest scores on each measure, though children with DLD + SSD performed similarly to TD children on encoding when vocabulary was included as a covariate. Children with SSD only outperformed children with DLD + SSD on competence and transcoding, and these two groups performed similarly on memory. A separate exploratory analysis using a 3 × 3 multivariate analysis of covariance revealed that children with DLD + SSD were more likely than children in the other groups to produce weak wordinitial stress and vowel errors during syllable repetition. Conclusion: Children with SSD and DLD + SSD exhibit underlying phonological deficits on the SRT compared to TD children. Results support the claim that memory and encoding are deficits in SSD. In addition, transcoding deficits were identified among children with no known oromotor impairment. Therefore, more research is required to identify the relationship between SRT performance and explicit measures of phonological processing. [ABSTRACT FROM AUTHOR]

Ionic liquid ion sources utilize electric fields to evaporate and accelerate ions and ion clusters to ∼1 keV energies. Ion clusters may dissociate after evaporation, which is not a well-characterized phenomenon and has relevant consequences in many applications. We measure the dissociation rate-constants of ion clusters for several ionic liquids. It is found that ion cluster dissociation occurs on timescales of the order of 1–5 μs and follows a constant-rate equation in the region outside the ion source. Using the measured rate-constants, we estimate the post-emission ion cluster temperatures. We also qualify the way the electric field enhances the rate-constants. Finally, our work supports the hypothesis that ion clusters with many degrees of freedom have lower dissociation rates. [ABSTRACT FROM AUTHOR]

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported. Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0–2 /DMF for years 3–9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed. Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0–2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6–0.8 and 0.9–2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was −1.32% (range −1.60% to −1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation. Conclusions: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS. Trial registration: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM). [ABSTRACT FROM AUTHOR]

Objectives: Eating disorders are common and serious conditions affecting up to 4% of the population. The mortality rate is high. Despite the seriousness and prevalence of eating disorders in children and adolescents, no Canadian practice guidelines exist to facilitate treatment decisions. This leaves clinicians without any guidance as to which treatment they should use. Our objective was to produce such a guideline. Methods: Using systematic review, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, and the assembly of a panel of diverse stakeholders from across the country, we developed high quality treatment guidelines that are focused on interventions for children and adolescents with eating disorders. Results: Strong recommendations were supported specifically in favour of Family-Based Treatment, and more generally in terms of least intensive treatment environment. Weak recommendations in favour of Multi-Family Therapy, Cognitive Behavioural Therapy, Adolescent Focused Psychotherapy, adjunctive Yoga and atypical antipsychotics were confirmed. Conclusions: Several gaps for future work were identified including enhanced research efforts on new primary and adjunctive treatments in order to address severe eating disorders and complex co-morbidities. [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile.Objectives: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis.Methods: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability.Results: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).Conclusions: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events.Clinical Trials Registration: ClinicalTrials.gov (NCT03093324). [ABSTRACT FROM AUTHOR]

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported. Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0–2 /DMF for years 3–9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed. Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0–2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6–0.8 and 0.9–2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was –1.32% (range –1.60% to –1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation. Conclusions: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS. [ABSTRACT FROM AUTHOR]