Search

Abstract Radiopharmaceutical therapy using $$\upalpha$$ α -emitting $$^{225}$$ 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with $$\upalpha$$ α -sensitive detection devices can measure radioactivity distributions at 20–40 $$\upmu {\hbox {m}}$$ μ m resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative $$\upalpha$$ α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and $$^{213}$$ 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous $$^{225}$$ 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. $$^{225}$$ 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following $$^{225}$$ 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

Abstract Spontaneous pneumomediastinum (SPM) is a rare condition in children and young adults that raises concern for esophageal perforation or extension of an air leak, resulting in admissions with multiple interventions performed. To assess our outcomes, and to evaluate our resource utilization, we reviewed our experience with SPM. We conducted a retrospective review of SPM cases in patients aged 5–25 years old occurring between 2011 and 2021 at a single academic tertiary care center. Clinical, demographic, and outcome variables were collected and analyzed, and cohorts were compared using Fischer’s Exact Test and Welch’s T Test. 166 SPM cases were identified—all of which were Emergency Department (ED) presentations. 84% of the cases were admitted. 70% had Computerized Tomography (CT) scans, with no defined criteria for imaging. Comparison of floor admissions with discharges from the ED showed no significant difference in presenting symptoms, demographics, or outcomes between the two groups. Recurrence was noted in 4 patients with a range of 5.9 months–4.9 years from the initial episode. In the largest SPM study in the pediatric and young adult population, we noted no significant difference in management or outcomes in admitted or ED discharge patients nor those with CT imaging. Our results suggest that a large number of SPM can be managed safely with discharge from the ED.

Abstract Epithelia maintain a functional barrier during tissue turnover while facing varying mechanical stress. This maintenance requires both dynamic cell rearrangements driven by actomyosin-linked intercellular adherens junctions and ability to adapt to and resist extrinsic mechanical forces enabled by keratin filament-linked desmosomes. How these two systems crosstalk to coordinate cellular movement and mechanical resilience is not known. Here we show that in stratifying epithelia the polarity protein aPKCλ controls the reorganization from stress fibers to cortical actomyosin during differentiation and upward movement of cells. Without aPKC, stress fibers are retained resulting in increased contractile prestress. This aberrant stress is counterbalanced by reorganization and bundling of keratins, thereby increasing mechanical resilience. Inhibiting contractility in aPKCλ−/− cells restores normal cortical keratin networks but also normalizes resilience. Consistently, increasing contractile stress is sufficient to induce keratin bundling and enhance resilience, mimicking aPKC loss. In conclusion, our data indicate that keratins sense the contractile stress state of stratified epithelia and balance increased contractility by mounting a protective response to maintain tissue integrity.

Abstract We examined the neurocomputational mechanisms in which male adolescents make food and physical activity decisions and how those processes are influenced by body weight and physical activity levels. After physical activity and dietary assessments, thirty-eight males ages 14–18 completed the behavioral rating and fMRI decision tasks for food and physical activity items. The food and physical activity self-control decisions were significantly correlated with each other. In both, taste- or enjoyment-oriented processes were negatively associated with successful self-control decisions, while health-oriented processes were positively associated. The correlation between taste/enjoyment and healthy attribute ratings predicted actual laboratory food intake and physical activities (2-week activity monitoring). fMRI data showed the decision values of both food and activity are encoded in the ventromedial prefrontal cortex, suggesting both decisions share common reward value-related circuits at the time of choice. Compared to the group with overweight/obese, the group with normal weight showed stronger brain activations in the cognitive control, multisensory integration, and motor control regions during physical activity decisions. For both food and physical activity, self-controlled decisions utilize similar computational and neurobiological mechanisms, which may provide insights into how to promote healthy food and physical activity decisions.

Abstract Cognitive functions are well-preserved for some older individuals, but the underlying brain mechanisms remain disputed. Here, 5-year longitudinal 3-back in-scanner and offline data classified individuals in a healthy older sample (baseline age = 64–68 years) into having stable or declining working-memory (WM). Consistent with a vital role of the prefrontal cortex (PFC), WM stability or decline was related to maintained or reduced longitudinal PFC functional responses. Subsequent analyses of imaging markers of general brain maintenance revealed higher levels in the stable WM group on measures of neurotransmission and vascular health. Also, categorical and continuous analyses showed that rate of WM decline was related to global (ventricles) and local (hippocampus) measures of neuronal integrity. Thus, our findings support a role of the PFC as well as general brain maintenance in explaining heterogeneity in longitudinal WM trajectories in aging.

Abstract Targeted radiopharmaceutical therapy with alpha-particle emitters (αRPT) is advantageous in cancer treatment because the short range and high local energy deposition of alpha particles enable precise radiation delivery and efficient tumor cell killing. However, these properties create sub-organ dose deposition effects that are not easily characterized by direct gamma-ray imaging (PET or SPECT). We present a computational procedure to determine the spatial distribution of absorbed dose from alpha-emitting radionuclides in tissues using digital autoradiography activity images from an ionizing-radiation quantum imaging detector (iQID). Data from 211At-radioimmunotherapy studies for allogeneic hematopoietic cell transplantation in a canine model were used to develop these methods. Nine healthy canines were treated with 16.9–30.9 MBq 211At/mg monoclonal antibodies (mAb). Lymph node biopsies from early (2–5 h) and late (19–20 h) time points (16 total) were obtained, with 10–20 consecutive 12-µm cryosections extracted from each and imaged with an iQID device. iQID spatial activity images were registered within a 3D volume for dose-point-kernel convolution, producing dose-rate maps. The accumulated absorbed doses for high- and low-rate regions were 9 ± 4 Gy and 1.2 ± 0.8 Gy from separate dose-rate curves, respectively. We further assess uptake uniformity, co-registration with histological pathology, and requisite slice numbers to improve microscale characterization of absorbed dose inhomogeneities in αRPT.

Abstract Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty, typically necessitating surgical intervention and prolonged antimicrobial therapy. Currently, there is no perfect assay for PJI diagnosis. Proteomic profiling of sonicate fluid has the potential to differentiate PJI from non-infectious arthroplasty failure (NIAF) and possibly clinical subsets of PJI and/or NIAF. In this study, 200 sonicate fluid samples, including 90 from subjects with NIAF (23 aseptic loosening, 35 instability, 10 stiffness, five osteolysis, and 17 other) and 110 from subjects with PJI (40 Staphylococcus aureus, 40 Staphylococcus epidermidis, 10 Staphylococcus lugdunensis, 10 Streptococcus agalactiae, and 10 Enterococcus faecalis) were analyzed by proximity extension assay using the 92 protein Inflammation Panel from Olink Proteomics. Thirty-seven of the 92 proteins examined, including CCL20, OSM, EN-RAGE, IL8, and IL6, were differentially expressed in PJI versus NIAF sonicate fluid samples, with none of the 92 proteins differentially expressed between staphylococcal versus non-staphylococcal PJI, nor between the different types of NIAF studied. IL-17A and CCL11 were differentially expressed between PJI caused by different bacterial species, with IL-17A detected at higher levels in S. aureus compared to S. epidermidis and S. lugdunensis PJI, and CCL11 detected at higher levels in S. epidermidis compared to S. aureus and S. agalactiae PJI. Receiver operative characteristic curve analysis identified individual proteins and combinations of proteins that could differentiate PJI from NIAF. Overall, proteomic profiling using this small protein panel was able to differentiate between PJI and NIAF sonicate samples and provide a better understanding of the immune response during arthroplasty failure.

Abstract Acid sphingomyelinase deficiency (ASMD), historically known as Niemann–Pick disease (NPD) types A, A/B, and B, is a rare, progressive, potentially fatal lysosomal storage disease with a spectrum of phenotypes. Little is known about how ASMD symptoms affect the lives of patients and their caregivers. In a cross-sectional qualitative study conducted in the US and UK, and in collaboration with the National Niemann–Pick Disease Foundation (US) and Niemann–Pick UK, we investigated the symptom experience of patients with ASMD types B and A/B and explored how the disease impacts their and their caregivers’ lives. The study included 17 adult patients (mean age 38.7 years, 12 female), three caregivers of adults with ASMD, 12 pediatric/adolescent patients with ASMD (mean age 10.5 years, six female), and 12 caregivers of pediatric/adolescent patients with ASMD. The most commonly reported disease manifestations were respiratory (n = 26, 89.7%), abdominal (n = 25, 86.2%), and musculoskeletal symptoms (n = 23, 79.3%); excessive bleeding or bruising (n = 20, 69%); fatigue (n = 20, 69%); gastrointestinal symptoms (n = 18, 62.1%); and headache (n = 15, 51.7%). ASMD was reported to negatively impact patients’ physical function (n = 23, 79.3%), self-esteem (n = 18, 62.1%), emotions (n = 16, 55.2%), social function and relationships (n = 16, 55.2%), and personal care (n = 9, 31%). Providing care for individuals with ASMD negatively affected caregivers’ emotional well-being (n = 12, 80%), social function (n = 4, 26.7%), relationships (n = 6, 40%), and financial security (n = 7, 46.7%). The physical toll of providing care, the need for lifestyle changes, and the responsibility for making medical decisions added to the burden for caregivers. Alternatively, some caregivers noted that caring for a loved one enhanced their spirituality, providing them with a different outlook on life and a deeper personal resolve. This study showed that ASMD is a substantial burden for patients and caregivers, with long-term physical, emotional, social, and financial impacts. The study confirmed commonly known manifestations of ASMD, especially respiratory problems, but also identified less recognized ones, such as dermatological complications. The data collected and insight gained from this study should enhance clinical care, help evaluate new treatments, and inform health care decision making for patients with ASMD.

Abstract Acute kidney injury (AKI) is a severe complication of coronavirus disease (COVID-19) that negatively affects its outcome. Concern had been raised about the potential effect of renin–angiotensin–aldosterone system (RAAS) blockades on renal outcomes in COVID-19 patients. However, the association between RAAS blockade use and incident AKI in COVID-19 patients has not been fully understood. We investigated the association between RAAS blockade exposure and COVID-19-related AKI in hospitalized patients through meta-analysis. Electronic databases were searched up to 24th December 2020. Summary estimates of pooled odds ratio (OR) of COVID-19-related AKI depending on RAAS blockade exposure were obtained through random-effects model. The random-effect meta-analysis on fourteen studies (17,876 patients) showed that RAAS blockade use was significantly associated with increased risk of incident AKI in hospitalized COVID-19 patients (OR 1.68; 95% confidence interval 1.19–2.36). Additional analysis showed that the association of RAAS blockade use on COVID-19-related AKI remains significant even after stratification by drug class and AKI severity. RAAS blockade use is significantly associated with the incident AKI in hospitalized COVID-19 patients. Therefore, careful monitoring of renal complications is recommended for COVID-19 patients with recent RAAS blockade use due to the potential risk of AKI.

Abstract Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (−0.2 ± 0.19 nmol/L, p = 0.0327; respectively −0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these real-world patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.

Electrically evoked frequency-following responses (eFFRs) provide insight in the phase-locking ability of brainstem of cochlear-implant (CI) users. eFFRs can potentially be used to gain insight in the individual differences in the biological limitation on temporal encoding of the electrically stimulated auditory pathway, which can be inherent to the electrical stimulation itself and/or the degenerative processes associated with hearing loss. One of the major challenge of measuring eFFRs in CI users is the process of isolating the stimulation artifact from the neural response, as both the response and the artifact overlap in time and have similar frequency characteristics. Here we introduce a new artifact removal method based on template subtraction that successfully removes the stimulation artifacts from the recordings when CI users are stimulated with pulse trains from 128 to 300 pulses per second in a monopolar configuration. Our results show that, although artifact removal was successful in all CI users, the phase-locking ability of the brainstem to the different pulse rates, as assessed with the eFFR differed substantially across participants. These results show that the eFFR can be measured, free from artifacts, in CI users and that they can be used to gain insight in individual differences in temporal processing of the electrically stimulated auditory pathway.

Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with ones partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybins acute effects (4-6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1-2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via Oceanic Boundlessness). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

Radiopharmaceutical therapy using α -emitting 225 Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with α -sensitive detection devices can measure radioactivity distributions at 20-40 μm resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [225Ac]Ac-Macropa-PEG4-YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [225Ac]Ac-Macropa-PEG4-YS5 were sacrificed at 24 h and 168 h post-injection for quantitative α -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and 213 Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous 225 Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. 225 Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following 225 Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived negative psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe-e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use-and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53%