Citations

Abstract Objective To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long‐term patient health outcomes. Background and Methods This was an exploratory analysis of patients with TBI who were enrolled in the American Registry for Migraine Research (ARMR), a multicenter, prospective, longitudinal patient registry composed of patients with International Classification of Headache Disorders, 3rd edition (ICHD‐3)–defined headache diagnoses. The ARMR study enrolled 2,707 patients between February 1, 2016 and May 6, 2020, 565 of whom qualified for this analysis. Those with headaches prior to their TBI were compared to those without headaches prior to their TBI for ICHD‐3 diagnoses, headache frequency and intensity, headache‐related disability (Migraine Disability Assessment score), symptoms of anxiety (General Anxiety Disorder [GAD‐7]), depression (two items from Patient Health Questionnaire‐9), post‐traumatic stress disorder (PTSD), cutaneous allodynia (12‐item Allodynia Symptom Checklist [ASC‐12]), cognitive dysfunction (Migraine Attacks Subjective Cognitive Impairments Scale [Mig‐SCog]), pain interference (Patient‐Reported Outcomes Measurement Information System‐Pain Interference), and work productivity (Work Productivity and Activity Impairment). Results Among 565 participants with TBI, 350 had headaches prior to their TBI. Those with pre‐TBI headaches were less likely to receive a diagnosis of post‐traumatic headache (PTH; 14/350 [4.0%] vs. 21/215 [9.8%], p = 0.006), even though 25.7% reported new or worsening headaches within 7 days of their TBI. Those with pre‐TBI headaches had higher ASC‐12 scores (2.4 ± 3.5 vs. 1.8 ± 3.4, p = 0.030), Mig‐SCog scores (9.3 ± 4.7 vs. 8 ± 4.9, p = 0.004), and GAD‐7 scores (6.9 ± 5.1 vs. 6.2 ± 5.4, p = 0.039), and were more likely to have a migraine diagnosis (335/350 [95.7%] vs. 192/215 [89.3%], p = 0.003). Conclusions Those with headaches prior to TBI are less likely to receive a diagnosis of PTH. They have more severe symptoms of cutaneous allodynia, cognitive impairment, and generalized anxiety. This analysis suggests that pre‐TBI headaches might impact post‐TBI headache diagnoses and associated features.

Abstract There is great interest in expanding the use of ultrasound (US), but new challenges exist with its application to lumbar facet–targeted procedures. The primary aim of this systematic review and meta-analysis was to determine the risk of incorrect needle placement associated with US–guided lumbar medial branch blocks (MBB) and facet joint injections (FJI) as confirmed by fluoroscopy or computerized tomography (CT). An a priori protocol was registered, and a database search was conducted. Inclusion criteria included all study types. Risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials and the National Heart, Lung, and Blood tool for assessing risk bias for observational cohort studies. Pooled analysis of the risk difference (RD) of incorrect needle placement was calculated. Pooled analysis of 7 studies demonstrated an 11% RD (P < 0.0009) of incorrect needle placement for US-guided MBB confirmed using fluoroscopy with and without contrast. Pooled analysis of 3 studies demonstrated a 13% RD (P < 0.0001) of incorrect needle placement for US-guided FJI confirmed using CT. The time to complete a single-level MBB ranged from 2.6 to 5.0 minutes. The certainty of evidence was low to very low. Ultrasound-guided lumbar MBB and FJI are associated with a significant risk of incorrect needle placement when confirmed by fluoroscopy or CT. The technical limitations of US and individual patient factors could contribute to the risk of incorrect needle placement.

Introduction Diabetes is one of the most common serious chronic health conditions in the USA. People living with diabetes face multiple barriers to optimal diabetes care, including gaps in access to medical care and self-management education, diabetes distress, and high burden of treatment. Community paramedics (CPs) are uniquely positioned to support multidisciplinary care for patients with diabetes by delivering focused diabetes self-management education and support and bridging the gaps between patients and the clinical and community resources they need to live well with their disease. Methods and analysis We will conduct a pragmatic single-arm prospective trial of a CP-led Diabetes Rescue, Engagement and Management (D-REM) programme that seeks to reduce diabetes distress. We will enrol 70 adults (≥18 years) with diabetes who have haemoglobin A1c (HbA1c)≥9.0%, experienced an emergency department (ED) visit or hospitalisation for any cause within the prior 6 months, and reside in areas with available CP support in Southeast Minnesota (Olmsted, Freeborn and Mower counties) and Northwest Wisconsin (Barron, Rusk and Dunn counties). Participants will be identified using Mayo Clinic electronic health records, contacted for consent and enrolled into the D-REM programme. Visit frequency will be individualised for each patient, but will be an average of four CP visits over the course of approximately 1 month. Outcomes will be change in diabetes distress (primary outcome), confidence in diabetes self-management, health-related quality of life, self-reported hypoglycaemia and hyperglycaemia, HbA1c, ED visits and hospitalisations. Outcomes will be assessed on enrolment, programme completion and 3 months after programme completion. Ethics and dissemination The study was approved by Mayo Clinic Institutional Review Board. Findings will be disseminated through peer-reviewed publications and presentations. If demonstrated to be successful, this model of care can be implemented across diverse settings and populations to support patients living with diabetes. Trial registration number NCT04385758 .

Abstract Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. Significance: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825

AbstractBackgroundCryptococcus spp. infection involving the central nervous system (CNS) is associated with poor outcomes. Current guidelines recommend repeating a cerebrospinal fluid (CSF) fungal culture after 2 weeks of treatment to evaluate for clearance. However, this practice has not clearly been associated with outcomes.ObjectivesWe sought to assess the relationship between CSF fungal clearance at 2 weeks and 12‐month mortality in patients with CNS cryptococcosis.MethodsThis is a retrospective cohort study from 2011 to 2020 of patients with CNS cryptococcosis. Factors associated with 12‐month mortality were assessed with Fisher’s exact test for categorical variables and Mann–Whitney test for continuous variables.ResultsAmong 51 patients with CNS cryptococcosis, 42 (82.4%) were initially CSF culture positive. Among 27 patients with follow‐up CSF culture at 2 weeks, 6 (22.2%) had a positive result. Factors associated with a positive CSF culture at 2 weeks were an initial CSF cryptococcal antigen titre ≥1:2560, fungaemia, and an elevated intracranial pressure requiring therapeutic lumbar punctures. The 12‐month mortality rate was 33.3%, and this was significantly associated with baseline fungaemia, extra‐CNS cryptococcal involvement and requirement of intensive care unit level of care. Lack of CSF culture clearance by 2 weeks was not associated with 12‐month mortality.ConclusionsCNS cryptococcosis has a high mortality rate. A markedly elevated CSF cryptococcal antigen, and opening CSF pressure was associated with lack of CSF culture clearance at 2 weeks of treatment. Severe disseminated disease and cryptococcemia were associated with 12‐month mortality.

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well‐studied. PURPOSE The purpose of this study was to investigate how obesity influences acute exercise responsiveness within skeletal muscle. METHODS Non‐obese (NO; n=19; 10F/9M; BMI=25.1 ± 2.8 kg/m 2 ) and Obese (O; n=21; 14F/7M; BMI=37.3 ± 4.6 kg/m 2 ) adults performed 30 minutes of single‐leg cycling at 70% of VO 2 peak. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3 and 6 hours post‐exercise to measure protein synthesis and gene expression. RESULTS The exercise‐induced fold change in mixed muscle protein synthesis trended (p=0.058) higher in NO (1.28 ± 0.54‐fold) compared to O (0.95 ± 0.42‐fold) and was inversely related to BMI (r=‐.374, p=0.027). RNA sequencing revealed 331 and 280 genes that were up or downregulated after exercise in NO and O, respectively. Gene set enrichment analysis showed O had blunted post‐exercise pathways related to MAPK signaling, chemokine‐mediated signaling, FC receptor mediated stimulation signaling, cell proliferation, apoptosis, and RNA polymerase II promotion. Quantitative polymerase chain reaction of select metabolic ( PGC1a, PGC1b, TFAM, PDK4, IRS, MAPK, and PRKAA1 ) and muscle growth ( SLC, TBC, MSTN, MyoD, TRIM32, FOX03, and FBXO3) genes were similar between groups 3 and 6 hours after exercise. Conclusion These data highlight several unique pathways in individuals with obesity that result in a blunted exercise response.

Radiation-associated sarcoma of the pelvis and/or sacrum (RASB) is a rare but challenging disease process associated with a poor prognosis. We hypothesized that patients with RASB would have worse surgical and oncologic outcomes than patients diagnosed with primary pelvic or sacral bone sarcomas. This was a retrospective, multi-institution, comparative analysis. We reviewed surgically treated patients from multiple tertiary care centers who were diagnosed with a localized RASB. We also identified a comparison group including all patients diagnosed with a primary localized pelvic or sacral osteosarcoma/spindle cell sarcoma of bone (POPS). There were 35 patients with localized RASB and 73 patients with POPS treated with surgical resection. Patients with RASB were older than those with POPS (57 years vs. 38 years, p < 0.001). Patients with RASB were less likely to receive chemotherapy (71% for RASB vs. 90% for POPS, p = 0.01). Seventeen percent of patients with RASB died in the perioperative period (within 90 days of surgery) as compared to 4% with POPS (p = 0.03). Five-year disease-specific survival (DSS) (31% vs. 54% p = 0.02) was worse for patients with RASB vs. POPS. There was no difference in 5-year local recurrence free survival (LRFS) or metastasis free survival (MFS). RASB and POPS present challenging disease processes with poor oncologic outcomes. Rates of perioperative mortality and 5-year DSS are worse for RASB when compared to POPS.

Abstract Background Neuropathic pain is a complex condition that can be refractory to conventional management and can cause persistent suffering in patients. Current pharmacologic treatments can provide temporary symptomatic relief; however, the mechanism of these therapies does not address the underlying cause of neuropathic pain. The use of injectable biologics for neuropathic pain has multiple proposed mechanisms for analgesia including attenuation of inflammatory mediated processes, arrest or delay of the degenerative process, inhibition of apoptotic pathways, and augmentation of the survival and recovery of injured and uninjured nerves. Study Design A systematic review of human studies involving the use of injectable biologics for neuropathic pain. Methods A comprehensive search of several data bases including Ovid MEDLINE ® and Epub Ahead of Print, In Process & Other Non-Indexed Citations and Daily, and Ovid Embase from inception to November 24, 2020. Results The initial search yielded 3,450 studies with an additional 6 studies identified through other resources. Twenty-seven studies were included after independent review by two of the investigators. The included studies assessed the efficacy of injectable biologics for the treatment of neuropathic pain defined as pain reduction. Secondary outcome measures included functional improvement as well as safety of the procedures. A qualitative assessment of the literature without meta-analysis was performed due to the heterogeneity of the data. Conclusion According to the GRADE criteria, there is very low certainty of evidence in support of the efficacy of injectable biologics for treatment of neuropathic pain. Future efforts should focus on creating a standardized methodology and study design with respect to preparation, dosage and route of administration of biologics. This will serve as a catalyst for higher quality randomized trials with generation of more useful data to help drive informed clinical decision making.

Abstract Background and study aims In patients with inflammatory bowel disease (IBD), endoscopically visible lesions with distinct borders can be considered for endoscopic resection. The role of endoscopic submucosal dissection (ESD) for these lesions is not well defined because of a paucity of data. We aimed to evaluate the outcomes of colorectal ESD of dysplastic lesions in patients with IBD across centers in the United States. Patients and methods This was a retrospective analysis of consecutive patients with IBD who were referred for ESD of dysplastic colorectal lesions at nine centers. The primary endpoints were the rates of en bloc resection and complete (R0) resection. The secondary endpoints were the rates of adverse events and lesion recurrence. Results A total of 45 dysplastic lesions (median size 30mm, interquartile range [IQR] 23 to 42 mm) in 41 patients were included. Submucosal fibrosis was observed in 73 %. En bloc resection was achieved in 43 of 45 lesions (96 %) and R0 resection in 34 of 45 lesions (76 %). Intraprocedural perforation occurred in one patient (2.4 %) and was treated successfully with clip placement. Delayed bleeding occurred in four patients (9.8 %). No severe intraprocedural bleeding or delayed perforation occurred. During a median follow-up of 18 months (IQR 13 to 37 months), local recurrence occurred in one case (2.6 %). Metachronous lesions were identified in 11 patients (31 %). Conclusions ESD, when performed by experts, is safe and effective for large, dysplastic colorectal lesions in patients with IBD. Despite the high prevalence of submucosal fibrosis, en bloc resection was achieved in nearly all patients with IBD undergoing ESD. Careful endoscopic surveillance is necessary to monitor for local recurrence and metachronous lesions after ESD.

Abstract Antispike monoclonal antibody treatment of 180 B-cell-depleted patients with mild-to-moderate coronavirus disease 2019 (COVID-19) resulted in good outcomes overall, with only 12.2% progressing to severe disease, 9.4% requiring hospitalization, 0.6% requiring mechanical ventilation, no deaths within 30 days, and 1.8% developing persistent COVID-19. Antispike monoclonal antibodies appear effective in this immunocompromised population.