Training prediction models for individual risk assessment of postoperative complications after surgery for colorectal cancer.

BACKGROUND: The occurrence of postoperative complications and anastomotic leakage are major drivers of mortality in the immediate phase after colorectal cancer surgery. We trained prediction models for calculating patients' individual risk of complications based only on preoperatively available data in a multidisciplinary team setting. Knowing prior to surgery the probability of developing a complication could aid in improving informed decision-making by surgeon and patient and individualize surgical treatment trajectories. METHODS: All patients over 18 years of age undergoing any resection for colorectal cancer between January 1, 2014 and December 31, 2019 from the nationwide Danish Colorectal Cancer Group database were included. Data from the database were converted into Observational Medical Outcomes Partnership Common Data Model maintained by the Observation Health Data Science and Informatics initiative. Multiple machine learning models were trained to predict postoperative complications of Clavien-Dindo grade ≥ 3B and anastomotic leakage within 30 days after surgery. RESULTS: Between 2014 and 2019, 23,907 patients underwent resection for colorectal cancer in Denmark. A Clavien-Dindo complication grade ≥ 3B occurred in 2,958 patients (12.4%). Of 17,190 patients that received an anastomosis, 929 experienced anastomotic leakage (5.4%). Among the compared machine learning models, Lasso Logistic Regression performed best. The predictive model for complications had an area under the receiver operating characteristic curve (AUROC) of 0.704 (95%CI 0.683-0.724) and an AUROC of 0.690 (95%CI 0.655-0.724) for anastomotic leakage. CONCLUSIONS: The prediction of postoperative complications based only on preoperative variables using a national quality assurance colorectal cancer database shows promise for calculating patient's individual risk. Future work will focus on assessing the value of adding laboratory parameters and drug exposure as candidate predictors. Furthermore, we plan to assess the external validity of our proposed model.

In children and adolescents with temporomandibular disorder assembled with juvenile idiopathic arthritis - no association were found between pain and TMJ deformities using CBCT.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from temporomandibular disorder (TMD). Due to this, imaging diagnosis is crucial in JIA with non-symptomatic TM joint (TMJ) involvement. The aim of the study was to examine the association between clinical TMD signs/symptoms and cone-beam computed tomography (CBCT) findings of TMJ structural deformities in children and adolescents with JIA. METHODS: This cross-sectional study is part of a longitudinal prospective multi-centre study performed from 2015-2020, including 228 children and adolescents aged 4-16 years diagnosed with JIA, according to the International League of Associations for Rheumatology (ILAR). For this sub-study, we included the Bergen cohort of 72 patients (32 female, median age 13.1 years, median duration of JIA 4.5 years). Clinical TMD signs/symptoms were registered as pain on palpation, pain on jaw movement, and combined pain of those two. The severity of TMJ deformity was classified as sound (no deformity), mild, or moderate/severe according to the radiographic findings of CBCT. RESULTS: Of 72 patients, 21 (29.2%) had pain on palpation at and around the lateral pole, while 41 (56.9%) had TMJ pain upon jaw movement and 26 (36.1%) had pain from both. Of 141 TMJs, 18.4% had mild and 14.2% had moderate/severe structural deformities visible on CBCT. CBCT findings were not significantly associated with either the pain on palpation or the pain on jaw movement. A significant difference was found between structural deformities in CBCT and the combined pain outcome (pain at both palpation and movement) for both TMJs for the persistent oligoarticular subtype (p = 0.031). CONCLUSIONS: There was no association between painful TMD and CBCT imaging features of the TMJ in patients with JIA, but the oligoarticular subtype of JIA, there was a significant difference associated with TMJ pain and structural CBCT deformities.

Prevalence of temporomandibular disorder in children and adolescents with juvenile idiopathic arthritis - a Norwegian cross- sectional multicentre study.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer pain from temporomandibular disorder (TMD). Still, routines for the assessment of temporomandibular joint (TMJ) pain in health and dental care are lacking. The aims of this study were to examine the prevalence of TMD in children and adolescents with JIA compared to their healthy peers and to investigate potential associations between JIA and TMD. METHODS: This comparative cross-sectional study is part of a longitudinal multicentre study performed during 2015-2020, including 228 children and adolescents aged 4-16 years with a diagnosis of JIA according to the ILAR criteria. This particular substudy draws on a subset of data from the first study visit, including assessments of TMD as part of a broader oral health examination. Children and adolescents with JIA were matched with healthy controls according to gender, age, and centre site. Five calibrated examiners performed the clinical oral examinations according to a standardised protocol, including shortened versions of the diagnostic criteria for TMD (DC/TMD) and the TMJaw Recommendations for Clinical TMJ Assessment in Patients Diagnosed with JIA. Symptoms were recorded and followed by a clinical examination assessing the masticatory muscles and TMJs. RESULTS: In our cohort of 221 participants with JIA and 221 healthy controls, 88 (39.8%) participants with JIA and 25 (11.3%) healthy controls presented with TMD based on symptoms and clinical signs. Painful TMD during the last 30 days was reported in 59 (26.7%) participants with JIA vs. 10 (5.0%) of the healthy controls (p <  0.001). Vertical unassisted jaw movement was lower in participants with JIA than in controls, with means of 46.2 mm vs. 49.0 mm, respectively (p <  0.001). Among participants with JIA, a higher proportion of those using synthetic disease-modifying antirheumatic-drugs and biologic disease-modifying antirheumatic-drugs presented with painful masticatory muscles and TMJs at palpation. CONCLUSION: Symptoms and clinical signs of TMD were seen in approximately half of the JIA patients compared to about one fourth of their healthy peers. Painful palpation to masticatory muscles and decreased vertical unassisted jaw movement were more frequent in participants with JIA than among healthy controls and should be part of both medical and dental routine examinations in patients with JIA.

Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder.

Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

Diabetes and necrotizing soft tissue infections-A prospective observational cohort study: Statistical analysis plan.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are rare but carry a high morbidity and mortality. The multicenter INFECT project aims to improve the understanding of the pathogenesis, clinical characteristics, diagnosis, and prognosis of NSTIs. This article describes the study outline and statistical analyses that will be used. METHODS: Within the framework of INFECT project, patients with NSTI at 5 Scandinavian hospitals are enrolled in a prospective observational cohort study. The goal is to evaluate outcome and characteristics for patients with NSTI and diabetes compared to patients with NSTI without diabetes. The primary outcome is mortality at 90 days after inclusion. Secondary outcomes include days alive and out of ICU and hospital, SAPS II, SOFA score, infectious etiology, amputation, affected body area, and renal replacement therapy. Comparison in mortality between patients with diabetes type 1 and 2 as well as between insulin-treated and non-insulin-treated diabetes patients will be made. Clinical data for diabetic patients with NSTI will be reported. CONCLUSION: The study will provide important data on patients with NSTI and diabetes.

Necrotizing soft tissue infections - a multicentre, prospective observational study (INFECT): protocol and statistical analysis plan.

BACKGROUND: The INFECT project aims to advance our understanding of the pathophysiological mechanisms in necrotizing soft tissue infections (NSTIs). The INFECT observational study is part of the INFECT project with the aim of studying the clinical profile of patients with NSTIs and correlating these to patient-important outcomes. With this protocol and statistical analysis plan we describe the methods used to obtain data and the details of the planned analyses. METHODS: The INFECT study is a multicentre, prospective observational cohort study. Patients with NSTIs are enrolled in five Scandinavian hospitals, which are all referral centres for NSTIs. The primary outcomes are the descriptive variables of the patients. Secondary outcomes include identification of factors associated with 90-day mortality and amputation; associations between affected body part, maximum skin defect and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score and 90-day mortality; 90-day mortality in patients with and without acute kidney injury (AKI) and LRINEC score of six and above or below six; and association between affected body part at arrival and microbiological findings. Exploratory outcomes include univariate analyses of baseline characteristics associations with 90-day mortality. The statistical analyses will be conducted in accordance with the predefined statistical analysis plan. CONCLUSION: Necrotizing soft tissue infections result in severe morbidity and mortality. The INFECT study will be the largest prospective study in patients with NSTIs to date and will provide important data for clinicians, researchers and policy makers on the characteristics and outcomes of these patients.

A Multivariate Assessment of Clinical Contributions to the Severity of Perceived Dysfunction Measured by the Cumberland Ankle Instability Tool.

Chronic ankle instability is a common pathological consequence of ankle sprains. However, screening tools which assess self-reported dysfunction offer little insight into clinical factors which may be useful to improve deficits. The purpose of this study was to identify factors that contribute most to self-reported dysfunction. 93 individuals completed the Cumberland Ankle Instability Tool (CAIT), active range of motion, dynamic postural stability assessments, and an arthrometer inversion stress test to assess lateral ankle laxity and stiffness. Backwards selection linear-regression was used to identify the most parsimonious multifactorial model of the predictor variables' ability to predict questionnaire score. Ankle sprain history, dorsiflexion in knee flexion, medial-lateral dynamic postural stability, and inversion laxity talar tilt had the highest relationships with the CAIT. When combined in the backwards-regression model index, these predictors explained approximately 57% of the variability (r=0.76, R2=0.57, F=27.49, p<0.001) of the CAIT. Previous history, laxity, range of motion restrictions and balance together contributed to account for almost 60% of the variability in the CAIT. Clinical measures may have prognostic value assessing the severity of chronic ankle instability and allow clinicians to focus on specific deficiencies during rehabilitation programs.

Diagnostic accuracy of instrumented and manual talar tilt tests in chronic ankle instability populations.

Diagnostic accuracy of the talar tilt test is not well established in a chronic ankle instability (CAI) population. Our purpose was to determine the diagnostic accuracy of instrumented and manual talar tilt tests in a group with varied ankle injury history compared with a reference standard of self-report questionnaire. Ninety-three individuals participated, with analysis occurring on 88 (39 CAI, 17 ankle sprain copers, and 32 healthy controls). Participants completed the Cumberland Ankle Instability Tool, arthrometer inversion talar tilt tests (LTT), and manual medial talar tilt stress tests (MTT). The ability to determine CAI status using the LTT and MTT compared with a reference standard was performed. The sensitivity (95% confidence intervals) of LTT and MTT was low [LTT = 0.36 (0.23-0.52), MTT = 0.49 (0.34-0.64)]. Specificity was good to excellent (LTT: 0.72-0.94; MTT: 0.78-0.88). Positive likelihood ratio (+ LR) values for LTT were 1.26-6.10 and for MTT were 2.23-4.14. Negative LR for LTT were 0.68-0.89 and for MTT were 0.58-0.66. Diagnostic odds ratios ranged from 1.43 to 8.96. Both clinical and arthrometer laxity testing appear to have poor overall diagnostic value for evaluating CAI as stand-alone measures. Laxity testing to assess CAI may only be useful to rule in the condition.

Fe(III) distribution varies substantially within and between atherosclerotic plaques.

PURPOSE: Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. METHODS: Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. RESULTS: Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01). CONCLUSION: Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

Nasogastric vs. intravenous rehydration in children with gastroenteritis and refusal to drink: a randomized controlled trial.

BACKGROUND: Nasogastric rehydration therapy (NGRT) is the recommended therapy in moderately dehydrated children with gastroenteritis and refusal to drink, since it is supposed to be as effective if not better than intravenous rehydration therapy (IVRT). However, in clinical practice IVRT is often favored. We conducted a clinical trial to determine whether IVRT is not inferior to NGRT. PATIENTS AND METHODS: Children 3 months to 6 years of age with moderate dehydration and refusal to drink secondary to gastroenteritis were recruited. After clinical assessment of the degree of dehydration, patients were assigned randomly to receive either IVRT or NGRT over 6 h on the hospital ward. RESULTS: Recruitment did not yield the estimated number of patients. Mainly, non-enrollment was due to failure to obtain parental consent because IVRT was expected. 97 patients were enrolled in the study, 46 were randomized to NGRT and 51 to IVRT. There was no difference between IVRT and NGRT groups concerning length of hospital stay (2.2±1.1 days vs. 2.4±1.1 days), success of rehydration (78 vs. 76%) and adverse events. DISCUSSION: Since we had to terminate the study ahead of schedule due to a low recruiting rate, our results are not reliable. However, data from the literature shows that the widespread described superiority of NGRT over IVRT is seriously influenced by studies from developing countries questioning the applicability of the results to a setting available in high-income countries nowadays. CONCLUSION: Our study demonstrates the difficulties performing such a study in a high-income country to come to an objective and clearly evident final conclusion.

A computerised third molar surgery simulator--results of supervision by different professionals.

The purpose of the study was to investigate which supervisory approach afforded the most efficient learning method for undergraduate students in oral and maxillofacial surgery (OMS) using a computerised third molar surgery simulator. Fifth year dental students participated voluntarily in a randomised experimental study using the simulator. The amount of time required and the number of trials used by each student were evaluated as a measure of skills development. Students had the opportunity to practise the procedure until no further visible improvements were achieved. The study assessed four different types of supervision to guide the students. The first group was where they were supported by a teacher/specialist in OMS, the second by a teaching assistant, the third group practised without any supervision and the fourth received help from a simulator technician/engineer. A protocol describing assessment criteria was designed for this purpose, and a questionnaire was completed by all participating students after the study. The average number of attempts required to virtually remove a third molar tooth in the simulator was 1.44 times for the group supervised by an OMS teacher; 1.5 times for those supervised by a teaching assistant; 2.8 times for those who had no supervision; and 3.6 times when support was provided only by a simulator technician. The results showed that the most efficient experience of the students was when they were helped by an OMS teacher or a teaching assistant. In a time and cost-effective perspective, supervision by a teaching assistant for a third molar surgery simulator would be the optimal choice.

Which older adults maintain benefit from cognitive training? Use of signal detection methods to identify long-term treatment gains.

BACKGROUND: Cognitive training has been shown to improve memory in older adults; however, little is known about which individuals benefit from or respond best to training in the long term. Identification of responders' characteristics would help providers match cognitive interventions to individuals to improve their effectiveness. Signal detection methods may prove more informative than more commonly used analytic methods. The goal of the current study is to identify baseline characteristics of long-term treatment responders and of those able to maintain their initial benefit from cognitive training. METHODS: Participants were 120 non-demented, community-dwelling older adults who had participated in a cognitive training intervention. Tested predictors included both demographic and neurocognitive variables. Primary outcome variables were performance on measures of memory at one-year follow-up. RESULTS: Results of the signal detection analysis indicated that different neurocognitive performances predicted long-term effects of memory training and maintenance of initial treatment response according to different types of to-be-remembered material. Higher baseline scores on tests of associative memory, delayed verbal memory, attention, episodic memory, and younger age were found predictive of long-term response one year later. Higher associative memory scores and lower initial gains at the end of treatment (week 14) predicted successful maintenance of training gains at week 52. CONCLUSIONS: To derive long-term benefit from particular cognitive training programs, it appears necessary for older adults to have specific neurocognitive profiles. Further, inclusion of booster sessions to cognitive training programs may assist in maintenance of initial treatment gains.

Long-term successful healing of ulcerated necrobiosis lipoidica after topical therapy with becaplermin.

We report a case of chronic leg ulceration occurring in a patient with necrobiosis lipoidica (NL). After many topical treatments had failed to achieve healing, treatment with topical becaplermin was started, which resulted in rapid improvement and ultimately complete healing of the ulceration. Treatment of ulcerated NL is often disappointing. Many topical and systemic drugs have been tried. Becaplermin is a platelet-derived growth factor indicated for the treatment of neuropathic diabetic ulcers measuring < 50 mm in size. To our knowledge, this is only the second case reported in the literature of ulcerated NL successfully treated with becaplermin.

Which comorbid conditions and risk factors affect the outcome of and progression to total temporomandibular joint replacement?

Surgery is an effective modality to reduce pain and increase range of motion (ROM) in TMJ disorders. The aim of this study was to determine which comorbidities and risk factors affect outcomes and progression to total joint replacement (TJR). A retrospective cohort study of patients who underwent TJR between 2000- 2018 at MGH was conducted. Primary outcome was successful vs unsuccessful surgery. Success was defined as pain score ≤ 4 and ROM ≥ 30 mm; failure was defined as lack of either or both. Secondary outcome was differences between patients undergoing TJR only (group A) and those undergoing multiple surgeries progressing to TJR (group B). 99 patients (82 females, 17 males) were included. Mean follow-up was 4.1 years; mean age at first surgery was 34.2 (range 14-71) years. Unsuccessful outcomes were associated with high preoperative pain, low preoperative ROM, and higher number of surgeries. Male sex favored successful outcome. 75.0% group A and 47.6% group B had successful outcome. Group B had more females, higher postoperative pain, lower postoperative ROM, and used more opioids compared to group A. High preoperative pain, low preoperative ROM, and more surgeries were associated with poorer outcomes and frequent opioid use.

Anatomical and fMRI-network comparison of multiple DLPFC targeting strategies for repetitive transcranial magnetic stimulation treatment of depression.

BACKGROUND: The efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance. OBJECTIVE: In rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks. METHODS: Forty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed. RESULTS: Scalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response. CONCLUSION: EEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems.

A systematic approach to improve oral and maxillofacial surgery education.

To improve teaching quality and student satisfaction, a new curriculum in Oral Surgery was implemented at Karolinska Institutet in 2007. This paper describes the curriculum change as well as the results regarding quality, satisfaction, cost-effectiveness and workload for teachers and staff. To design the new curriculum, all members of the teaching staff participated in a series of group discussions where problems with the previous curriculum were identified and ideas on how to improve the curriculum were discussed. Cost-effectiveness was evaluated by comparing the number of teaching sessions between the new and the old curriculum. A questionnaire was used to investigate the staffs' perceived change in workload and teaching quality. The students' satisfaction and attitudes to learning was screened for by on-line questionnaires. The large amount of passive observational teaching was considered as the main problem with the old curriculum. Half of these sessions were replaced by either clinical seminars or demonstrations performed in an interactive form. Students rated the new curriculum as a clear improvement. Analyses of time and cost-effectiveness showed a decrease in teaching sessions by almost 50%. Generally, the teachers were more positive towards the changes compared to the non-teaching staff. The students rated the new type of learning activities relatively high, whilst the traditional observational teaching was seen as less satisfactory. They preferred to learn in a practical way and few indicated analytic or emotional preferences. The majority of the students reported a good alignment between the new course curriculum and the final exam.

Fentanyl Test Strip Use and Overdose History among Individuals on Medication for Opioid Use Disorder.

Background: The number of deaths from drug overdose in the United States has more than doubled in the past decade. In particular, drug overdose deaths involving fentanyl have doubled every year since 2013. Rapid fentanyl test strips (FTS) are a useful strategy for detecting traces of fentanyl in substances and have received overwhelming support from individuals with opioid-dependence. Methods: We investigated fentanyl use, knowledge of FTS, willingness to use FTS, and overdose history among a sample of 105 individuals currently on medication for opioid use disorder (MOUD). Results: Results showed that the majority (63%) of the sample had experienced a non-fatal overdose and that 85% of participants were willing to use FTS. The majority of participants reported concern about fentanyl in their drug supply (70%) and 77% reported likelihood of past unintentional fentanyl use. Of note, only about half (47%) of participants knew of FTS prior to being surveyed, and only 17% reported ever using FTS. Conclusion: These results expand on previous literature that documents high levels of willingness, yet low uptake of FTS among individuals on MOUD. Widespread education about FTS, in addition to the implementation of the use of FTS, is a highly promising and critical primary prevention alternative to overdose treatment and/or death due to fentanyl.

Targeting location relates to treatment response in active but not sham rTMS stimulation.

BACKGROUND: Precise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression. OBJECTIVE: To use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations. METHODS: An imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks. RESULTS: The average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome. CONCLUSION: These results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans.

Novel packages of viral and self-antigens are generated during apoptosis.

Immune context is an essential determinant of the host response to potential autoantigens. The clustering of the autoantigens targeted in systemic lupus erythematosus within surface blebs of apoptotic cells generates high concentrations of autoantigen within discrete subcellular packages. We demonstrate here that when apoptosis is induced by Sindbis virus infection, viral antigens and autoantigens cocluster exclusively in small surface blebs of apoptotic cells. The surface of these blebs is rich in viral glycoproteins, and virions can be seen blebbing from their surface. We propose that these blebs of mixed foreign and self-origin define a novel immune context that may challenge self-tolerance.