Comparison of Pericapsular Nerve Group and Lateral Quadratus Lumborum Blocks for Analgesia after Primary Total Hip Arthroplasty: A Randomized Controlled Trial.

Introduction: The quadratus lumborum block (QLB) and the pericapsular nerve group (PENG) block both provide effective postoperative analgesia after hip surgery while minimizing impact on motor function. This study aimed to compare QLB and PENG in patients undergoing primary total hip arthroplasty. Methods: This superiority trial randomized patients scheduled for elective total hip arthroplasty to receive a lateral QLB or PENG with lateral femoral cutaneous nerve blocks for postoperative analgesia. Perioperative analgesic protocols were standardized. The primary outcome was postoperative cumulative opioid consumption at 72 hours. Secondary outcome was postoperative pain scores. Additional outcomes of interest included time to first ambulation, length of stay, patient reported outcome measures, and opioid-related side effects. Results: This trial consented and randomized 106 subjects and 101 were included in analysis: PENG (n=50), QLB (n=51). Mean (95% CI) opioid consumption (IV MME) in the first 72 hours did not differ between PENG [109.6 (93.6, 125.6)] and QL [92.3 (76.6, 107.9)] groups (p=0.129) There were no significant differences between treatment arms in average pain score, time to ambulation, distance ambulated, rate of same day discharge, or hospital length of stay. There were also no differences in patient reported outcomes using HOOS-JR and PROMIS-10 scores. Conclusion: Patients undergoing primary THA receiving preoperative PENG vs QLB had similar opioid consumption, pain scores, time to ambulation, and hospital length of stay. Both QL and PENG blocks are analgesic options in patients undergoing primary THA. Clinical Trials Registration: NCT05710107; www.ClinicalTrial.gov IRB Protocol ID: Pro00124880. Key message: Pericapsular nerve group (PENG) block may provide analgesia after hip arthroplasty and improve early functional recovery. This study evaluated postoperative opioid consumption in patients randomized to PENG or lateral quadratus lumborum block (QLB).Opioid consumption, pain scores, motor recovery, and functional outcome measures did not differ in patients randomized to PENG vs lateral QLB.PENG and lateral QLBs are analgesic options following total hip arthroplasty with similar rates of same day discharge.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Safety and efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors: A single center experience.

Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.

Image-Guided Transbronchial Pulmonary Cryoablation with a Flexible Cryoprobe in Swine: Performance and Radiology-Pathology Correlation.

PURPOSE: To evaluate the performance of a prototype flexible transbronchial cryoprobe compared with that of percutaneous transthoracic cryoablation and to define cone-beam computed tomography (CT) imaging and pathology cryolesion features in an in vivo swine model. MATERIALS AND METHODS: Transbronchial cryoablation was performed with a prototype flexible cryoprobe (3 central and 3 peripheral lung ablations in 3 swine) and compared with transthoracic cryoablation performed with a commercially available rigid cryoprobe (2 peripheral lung ablations in 1 swine). Procedural time and cryoablation success rates for endobronchial navigation and cryoneedle deployment were measured. Intraoperative cone-beam CT imaging features of cryolesions were characterized and correlated with gross pathology and hematoxylin and eosin-stained sections of the explanted cryolesions. RESULTS: The flexible cryoprobe was successfully navigated and delivered to each target through a steerable guiding sheath (6/6). At 4 minutes after ablation, 5 of 6 transbronchial and 2 of 2 transthoracic cryolesions were visible on cone-beam CT. The volumes on cone-beam CT images were 55.5 cm3 (SE ± 8.0) for central transbronchial ablations (n = 2), 72.5 cm3 (SE ± 8.1) for peripheral transbronchial ablations (n = 3), and 79.5 cm3 (SE ±11.6) for peripheral transthoracic ablations (n = 2). Pneumothorax developed in 1 animal after transbronchial ablation and during ablation in the transthoracic cryoablation. Images of cryoablation zones on cone-beam CT correlated well with the matched gross pathology and histopathology sections of the cryolesions. CONCLUSIONS: Transbronchial cryoablation with a flexible cryoprobe, delivered through a steerable guiding sheath, is feasible. Transbronchial cryoablation zones are imageable with cone-beam CT, with gross pathology and histopathology similar to those of transthoracic cryoablation.

Strength, power and aerobic capacity of transgender athletes: a cross-sectional study.

OBJECTIVE: The primary objective of this cross-sectional study was to compare standard laboratory performance metrics of transgender athletes to cisgender athletes. METHODS: 19 cisgender men (CM) (mean±SD, age: 37±9 years), 12 transgender men (TM) (age: 34±7 years), 23 transgender women (TW) (age: 34±10 years) and 21 cisgender women (CW) (age: 30±9 years) underwent a series of standard laboratory performance tests, including body composition, lung function, cardiopulmonary exercise testing, strength and lower body power. Haemoglobin concentration in capillary blood and testosterone and oestradiol in serum were also measured. RESULTS: In this cohort of athletes, TW had similar testosterone concentration (TW 0.7±0.5 nmol/L, CW 0.9±0.4 nmol/), higher oestrogen (TW 742.4±801.9 pmol/L, CW 336.0±266.3 pmol/L, p=0.045), higher absolute handgrip strength (TW 40.7±6.8 kg, CW 34.2±3.7 kg, p=0.01), lower forced expiratory volume in 1 s:forced vital capacity ratio (TW 0.83±0.07, CW 0.88±0.04, p=0.04), lower relative jump height (TW 0.7±0.2 cm/kg; CW 1.0±0.2 cm/kg, p<0.001) and lower relative V̇O2max (TW 45.1±13.3 mL/kg/min/, CW 54.1±6.0 mL/kg/min, p<0.001) compared with CW athletes. TM had similar testosterone concentration (TM 20.5±5.8 nmol/L, CM 24.8±12.3 nmol/L), lower absolute hand grip strength (TM 38.8±7.5 kg, CM 45.7±6.9 kg, p=0.03) and lower absolute V̇O2max (TM 3635±644 mL/min, CM 4467±641 mL/min p=0.002) than CM. CONCLUSION: While longitudinal transitioning studies of transgender athletes are urgently needed, these results should caution against precautionary bans and sport eligibility exclusions that are not based on sport-specific (or sport-relevant) research.

The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues.

Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.

Improvements in networking processes for hip or knee revision arthroplasty: a silver lining of the COVID-19 pandemic.

BACKGROUND: Improvements in outcomes following hip and knee revision arthroplasties have been demonstrated following the introduction of specialised orthopaedic services in the form of 'hub and spoke' networking models. In light of the COVID-19 pandemic, these networks have undergone some inevitable adaptations. We investigated the impact of recent adaptations on the performance of our regional revision arthroplasty network. METHODS: A retrospective review of all referrals that were discussed at our regional revision arthroplasty meeting, over 2 separate phases, was undertaken. Phase 1 included data between March 2018 and April 2019, representing an interval prior to COVID-19 pandemic. Phase-2 included data between September 2020 and March 2021 (during COVID-19 pandemic). Data were collected from East Midland South Orthopaedic Network (EMSSON) database and included data relating to indication and time to revision surgery, surgeon's proposal plan, network proposal plan, and executed definitive plan. We compared and analysed network performance between 2 phases. RESULTS: In phase 1, 99 cases were discussed in EMSSON meetings, equating to 35.7% of the region's revision arthroplasty volume, according to the National Joint Registry (NJR) records. Plan alterations were recommended in 48/99 cases (48.5%), of which 41/48 (85.4%) were adhered to. Phase 2 included 98 discussed cases, equating to 81.6% of the region's revision arthroplasty volume. Plan alterations were recommended in 20/98 cases (20.4%), all of which were adhered to (100%). Adherence to recommended adaptations showed significant improvement (p < 0.03). CONCLUSIONS: Based upon our observations, a greater volume and proportion of revision arthroplasty cases are now being discussed. Adherence to MDT recommendations has significantly improved following the described adaptations. The number of recommended adaptations to management plans have decreased, indicating an educational value of the network.Overall, these findings demonstrate a trend towards NHS England's target of 100% of revision arthroplasty cases undergoing MDT discussion.

Reducing the carbon footprint of cataract surgery: co-creating solutions with a departmental Delphi process.

BACKGROUND: Climate change is arguably the greatest threat to global health of the 21st century. Although cataract surgery is a major contributor to global greenhouse gas emissions, recent literature review identified a paucity of evidence-based strategies for improving the environmental impact of cataract services. Our study aimed to assess the effectiveness of a departmental Delphi process for improving cataract services' environmental sustainability. METHODS: All members of ophthalmology theatre teams in a UK teaching hospital were invited to participate in a three-stage Delphi process. Team members were surveyed for suggestions for reducing the department's environmental impact. Suggested interventions were refined during a plenary face-to-face discussion and ranked. The highest ranked interventions were combined into a mutually agreed action plan. Data on the economic and environmental cost of cataract services was collected prior to and six months after the Delphi process using the Eyefficiency mobile application. RESULTS: Twenty-three interventions were suggested by a range of staff cadres. Interventions were ranked by 24 team members. The 2nd, 4th, 5th, 8th and 11th ranked interventions were combined into an "Eco-packs" project in collaboration with suppliers (Bausch + Lomb), saving 675 kg of waste and 350 kg of CO2 equivalent annually. CONCLUSIONS: The Delphi process is an effective method for provoking departmental engagement with the sustainability agenda that we would encourage all ophthalmology departments to consider utilising. The baseline per case CO2 equivalent measured in our department was reproducible and could serve as a maximum benchmark to be improved upon.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

Enhanced recovery after surgery reduces length of stay after colorectal surgery in a small rural hospital in Ontario.

Introduction: Enhanced recovery after surgery (ERAS) programmes include pre-operative, intraoperative and post-operative clinical pathways to improve quality of patient care while reducing length of stay (LOS) and readmission. This study assessed the feasibility and outcomes of an ERAS protocol for colorectal surgery implemented over 2 years in a small, resource-challenged rural hospital. Methods: A prospective cohort study used retrospectively matched controls to assess the effect of ERAS on LOS in patients undergoing colorectal surgery in a small rural hospital in northern Ontario, Canada. ERAS patients were matched to two patients in the control group based on diagnosis, age and gender. Patients had open or laparoscopic colorectal surgeries, with those in the intervention group treated per ERAS protocol and given instructions on pre- and post-operative self-care. Results: Most of the 47 ERAS patients recruited to the study reported adherence to ERAS protocols before surgery. Adherence to protocol was strongest for chewing gum in the days after surgery. Most patients were sitting in a chair for their afternoon meal by the 1st day and most were walking down the hallway by the 2nd day. The control group had significantly higher (P < 0.001) malignant neoplasm of the colon (C18, 69% vs. 35%) and significantly lower malignant neoplasm of the rectum (C20, 0% vs. 5%). The control group had an average ln-transformed LOS that was significantly longer (exponentiated as 1.7 days) than ERAS patients (t-test, P < 0.001). Conclusion: This study found that ERAS could be implemented in a small rural hospital and provided evidence for a reduced LOS of approximately 2 days.

Résumé Introduction: Les programmes de réhabilitation améliorée après chirurgie (RAAC) comprennent des itinéraires cliniques préopératoires, peropératoires et postopératoires visant à améliorer la qualité des soins aux patients tout en réduisant la durée du séjour et les réadmissions. Cette étude a évalué la faisabilité et les résultats d'un protocole de RAAC pour la chirurgie colorectale mis en oeuvre pendant deux ans dans un petit hôpital rural aux ressources limitées. Méthodes: Une étude de cohorte prospective a utilisé des témoins appariés pour évaluer l'effet de la RAAC sur la durée du séjour des patients subissant une chirurgie colorectale dans un petit hôpital rural du nord de l'Ontario, au Canada. Les patients RAAC ont été appariés à deux patients du groupe témoin sur la base du diagnostic, de l'âge et du sexe. Les patients ont subi une chirurgie colorectale ouverte ou laparoscopique, et ceux du groupe d'intervention ont été traités selon le protocole de RAAC et ont reçu des instructions sur les soins auto-administrés pré et postopératoires. Résultats: La plupart des 47 patients RAAC recrutés pour l'étude ont déclaré adhérer aux protocoles de RAAC avant l'intervention chirurgicale. L'adhésion au protocole a été la plus forte pour la gomme à mâcher dans les jours qui ont suivi l'opération. La plupart des patients étaient assis sur une chaise pour le repas de l'après-midi dès le premier jour et la plupart marchaient dans le couloir dès le deuxième jour. Le groupe témoin présentait un taux significativement plus élevé (P < 0,001) de néoplasme malin du côlon (C18, 69% contre 35%) et un taux significativement plus faible de néoplasme malin du rectum (C20, 0% contre 5%). Le groupe de contrôle avait une durée moyenne de séjour transformée en Ln significativement plus longue (exponentielle de 1,7 jours) que les patients RAAC (test t, P < 0,001). Conclusion: Cette étude a montré que la RAAC pouvait être mise en oeuvre dans un petit hôpital rural et a fourni des preuves d'une réduction de la durée de séjour d'environ deux jours. Mots-clés: Réhabilitation améliorée après chirurgie (RAAC); durée du séjour; hôpitaux ruraux; chirurgie colorectale; Ontario; soins périopératoires.

A Motivational Interviewing Chatbot With Generative Reflections for Increasing Readiness to Quit Smoking: Iterative Development Study.

BACKGROUND: The motivational interviewing (MI) approach has been shown to help move ambivalent smokers toward the decision to quit smoking. There have been several attempts to broaden access to MI through text-based chatbots. These typically use scripted responses to client statements, but such nonspecific responses have been shown to reduce effectiveness. Recent advances in natural language processing provide a new way to create responses that are specific to a client's statements, using a generative language model. OBJECTIVE: This study aimed to design, evolve, and measure the effectiveness of a chatbot system that can guide ambivalent people who smoke toward the decision to quit smoking with MI-style generative reflections. METHODS: Over time, 4 different MI chatbot versions were evolved, and each version was tested with a separate group of ambivalent smokers. A total of 349 smokers were recruited through a web-based recruitment platform. The first chatbot version only asked questions without reflections on the answers. The second version asked the questions and provided reflections with an initial version of the reflection generator. The third version used an improved reflection generator, and the fourth version added extended interaction on some of the questions. Participants' readiness to quit was measured before the conversation and 1 week later using an 11-point scale that measured 3 attributes related to smoking cessation: readiness, confidence, and importance. The number of quit attempts made in the week before the conversation and the week after was surveyed; in addition, participants rated the perceived empathy of the chatbot. The main body of the conversation consists of 5 scripted questions, responses from participants, and (for 3 of the 4 versions) generated reflections. A pretrained transformer-based neural network was fine-tuned on examples of high-quality reflections to generate MI reflections. RESULTS: The increase in average confidence using the nongenerative version was 1.0 (SD 2.0; P=.001), whereas for the 3 generative versions, the increases ranged from 1.2 to 1.3 (SD 2.0-2.3; P<.001). The extended conversation with improved generative reflections was the only version associated with a significant increase in average importance (0.7, SD 2.0; P<.001) and readiness (0.4, SD 1.7; P=.01). The enhanced reflection and extended conversations exhibited significantly better perceived empathy than the nongenerative conversation (P=.02 and P=.004, respectively). The number of quit attempts did not significantly change between the week before the conversation and the week after across all 4 conversations. CONCLUSIONS: The results suggest that generative reflections increase the impact of a conversation on readiness to quit smoking 1 week later, although a significant portion of the impact seen so far can be achieved by only asking questions without the reflections. These results support further evolution of the chatbot conversation and can serve as a basis for comparison against more advanced versions.

Leveraging National Data and Regional Innovations to Right-Size Tobacco Treatment Policy for Behavioral Health in a Midwestern State.

BACKGROUND: People with mental health (MH) and substance use disorders (SUD) have high rates of tobacco use and tobacco-related mortality. They want to stop smoking and studies have shown they can quit, but few behavioral health facilities provide tobacco treatment. The purpose of this paper is to describe how a midwestern statewide behavioral health collaboration used regional data to pinpoint strengths and weaknesses in tobacco treatment trends, identified policies in neighboring states that were associated with high rates of tobacco treatment, and worked with state leaders to implement these policies to enhance treatment. METHODS: We used publicly available data from 2 SAMHSA annual national surveys of MH/SUD facilities to describe tobacco treatment services and policies in behavioral health facilities in Kansas and 3 neighboring states (Missouri, Nebraska and Oklahoma). We interviewed neighboring state leaders to identify policies they had implemented to boost tobacco recovery services in behavioral health. We collaborated with our state behavioral health agency to encourage adoption of similar policies. RESULTS: Using 7 years of survey data (2014-2020), rates for screening, counseling, and medications for tobacco dependence were highest in Oklahoma and Missouri facilities. Oklahoma had the highest percentages of facilities reporting smoke-free campuses. In all states, rates of tobacco service provision and smoke-free campuses were lower among SUD facilities than in MH facilities. State leaders associated several policies with high performance, including (a) requiring programs contracting with the state to conduct screening, provide counseling, and adopt smoke-free campuses (Oklahoma and Missouri); (b) state-based collection of tobacco treatment service provision data (Oklahoma); (c) providing facilities with free NRT for clients (Oklahoma); (d) setting benchmarks for service provision (Oklahoma); (e) comprehensive Medicaid coverage of cessation medications (Missouri). Upon review of these findings, Kansas behavioral health officials adopted a 2-year process to implement similar policies and are integrating tobacco treatment requirements into the state Certified Community Behavioral Health Clinic program. CONCLUSIONS: Summarizing and sharing freely-available data across states laid the groundwork for cross-border networking and policy change. State and federal agencies should integrate these policies into contracts and block grants to reduce tobacco-related disparities among individuals with behavioral health conditions.

The role of clinical imaging in oncology drug development: progress and new challenges.

In 2008, the role of clinical imaging in oncology drug development was reviewed. The review outlined where imaging was being applied and considered the diverse demands across the phases of drug development. A limited set of imaging techniques was being used, largely based on structural measures of disease evaluated using established response criteria such as response evaluation criteria in solid tumours. Beyond structure, functional tissue imaging such as dynamic contrast-enhanced MRI and metabolic measures using [18F]flourodeoxyglucose positron emission tomography were being increasingly incorporated. Specific challenges related to the implementation of imaging were outlined including standardisation of scanning across study centres and consistency of analysis and reporting. More than a decade on the needs of modern drug development are reviewed, how imaging has evolved to support new drug development demands, the potential to translate state-of-the-art methods into routine tools and what is needed to enable the effective use of this broadening clinical trial toolset. In this review, we challenge the clinical and scientific imaging community to help refine existing clinical trial methods and innovate to deliver the next generation of techniques. Strong industry-academic partnerships and pre-competitive opportunities to co-ordinate efforts will ensure imaging technologies maintain a crucial role delivering innovative medicines to treat cancer.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

Tenascin-R Autoimmunity: Isolated Tremor Reversed with Immunotherapy.

Autoimmune movement disorders are increasingly recognized, but isolated tremor is extremely rare. We describe a 70-year-old male with rapidly progressive, severe postural and intention tremor and weight loss. His cerebrospinal fluid was inflammatory and harbored a neural tissue-restricted antibody. The autoantigen was identified by immunoprecipitation and mass spectrometry and confirmed by antigen-specific assays to be specific for tenascin-R. He was investigated for cancer and diagnosed with follicular lymphoma that expressed tenascin-R suggesting a paraneoplastic origin; cancer treatment and immunotherapy led to complete recovery. With this individualized patient approach and antibody discovery, we expand the spectrum of antibodies accompanying autoimmune hyperkinetic movement disorders. ANN NEUROL 2023;94:502-507.

Extensive complex neocortical movement topography devolves to simple output following experimental stroke in mice.

The neocortex encodes complex and simple motor outputs in all mammalian species that have been tested. Given that changes in neocortical reorganization (and corresponding corticospinal output) have been implicated in long term motor recovery after stroke injury, there remains a need to understand this biology in order to expedite and optimize clinical care. Here, changes in the neocortical topography of complex and simple movement outputs were evaluated in mice following experimental middle cerebral artery occlusion (MCAo). Neocortical motor output was defined using long-duration parameters of intracortical microstimulation (LD-ICMS) based on area and spatial coordinates of separate motor output types to build upon our recent report in uninjured mice. LD-ICMS test sites that elicited complex (multi-joint) movement, simple (single skeletal joint) movement, as well as co-elicited FORELIMB + HINDLIMB responses were detected and recorded. Forelimb reaching behavior was assessed using the single pellet reaching (SPR) task. At 6 weeks post-surgery, behavioral deficits persisted and neocortical territories for separate movements exhibited differences in neocortical area, and spatial location, and differed between MCAo-Injured animals (i.e., the MCAo group) and Sham-Injured animals (i.e., the Control group). MCAo-Injury reduced neocortical area of complex movements while increasing area of simple movements. Limited effects of injury were detected for spatial coordinates of neocortical movements. Significant positive correlations were detected between final SPR performance and either area of complex retract or area of co-occurring FORELIMB + HINDLIMB sites.

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion.

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. To "benchmark" exhaustion in human Tregs, we used a method known to induce exhaustion in conventional T cells: expression of a tonic-signaling chimeric antigen receptor (TS-CAR). We found that TS-CAR-expressing Tregs rapidly acquired a phenotype that resembled exhaustion and had major changes in their transcriptome, metabolism, and epigenome. Similar to conventional T cells, TS-CAR Tregs upregulated expression of inhibitory receptors and transcription factors such as PD-1, TIM3, TOX and BLIMP1, and displayed a global increase in chromatin accessibility-enriched AP-1 family transcription factor binding sites. However, they also displayed Treg-specific changes such as high expression of 4-1BB, LAP, and GARP. DNA methylation analysis and comparison to a CD8+ T cell-based multipotency index showed that Tregs naturally exist in a relatively differentiated state, with further TS-CAR-induced changes. Functionally, TS-CAR Tregs remained stable and suppressive in vitro but were nonfunctional in vivo, as tested in a model of xenogeneic graft-versus-host disease. These data are the first comprehensive investigation of exhaustion in Tregs and reveal key similarities and differences with exhausted conventional T cells. The finding that human Tregs are susceptible to chronic stimulation-driven dysfunction has important implications for the design of CAR Treg adoptive immunotherapy strategies.

Brain exposure of osimertinib in patients with epidermal growth factor receptor mutation non-small cell lung cancer and brain metastases: A positron emission tomography and magnetic resonance imaging study.

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmax[brain] ) 22 min (median, Tmax[brain] ) after injection. Total volume of distribution (VT ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.