Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

The Assistant Clinical Research Coordinator Program: A Pathway for Recruitment in Radiation Oncology.

Purpose: Recruiting prospective physicians to radiation oncology can be challenging, because of limited familiarity with the field. The Assistant Clinical Research Coordinator (ACRC) program can help provide trainees early exposure to radiation oncology. Methods and Materials: The ACRC program involves hiring a college graduate to provide administrative and research support for faculty members. The program was developed with our institution's clinical trials office, which provided guidance on regulatory compliance and training. A structured selection process identifies top candidates, and a rigorous onboarding process ensures smooth transitions between ACRCs. We report characteristics and outcomes of ACRC employees and surveyed them to assess their program experience using a Likert scale. Results: From 2005 to 2023, the ACRC program paired 73 ACRCs with faculty. Most faculty (68%) are currently supported by ACRCs. In 2023, 113 applications were received for 4 positions. ACRCs have contributed to research publications (293 as coauthors and 43 as first authors) and taken on leadership roles in the department. Most program alumni have attended medical school (34 of 64 program graduates; 53%). Eight have chosen to specialize in radiation oncology (13%; 2 applying into radiation oncology, 1 in residency, and 5 attendings). Of the 25% of alumni who responded to our survey, 77% responded that the mentorship provided by the ACRC program was very or extremely effective in guiding their academic development. All respondents rated the research opportunities as good or excellent, and 77% rated the clinical experience opportunities as good or excellent. Most (77%) reported that the ACRC program had substantial or significant influence on their choice of career path. Conclusions: The ACRC program provides an opportunity to address recruitment challenges in radiation oncology by offering early exposure to the field, clinical research skills, and mentorship. With the strong interest in our job posting this year, there is potential to expand this program to other institutions.

On the acceptance, commissioning, and quality assurance of electron FLASH units.

Background & Purpose: FLASH or ultra-high dose rate (UHDR) radiation therapy (RT) has gained attention in recent years for its ability to spare normal tissues relative to conventional dose rate (CDR) RT in various preclinical trials. However, clinical implementation of this promising treatment option has been limited because of the lack of availability of accelerators capable of delivering UHDR RT. Commercial options are finally reaching the market that produce electron beams with average dose rates of up to 1000 Gy/s. We established a framework for the acceptance, commissioning, and periodic quality assurance (QA) of electron FLASH units and present an example of commissioning. Methods: A protocol for acceptance, commissioning, and QA of UHDR linear accelerators was established by combining and adapting standards and professional recommendations for standard linear accelerators based on the experience with UHDR at four clinical centers that use different UHDR devices. Non-standard dosimetric beam parameters considered included pulse width, pulse repetition frequency, dose per pulse, and instantaneous dose rate, together with recommendations on how to acquire these measurements. Results: The 6- and 9-MeV beams of an UHDR electron device were commissioned by using this developed protocol. Measurements were acquired with a combination of ion chambers, beam current transformers (BCTs), and dose-rate-independent passive dosimeters. The unit was calibrated according to the concept of redundant dosimetry using a reference setup. Conclusions: This study provides detailed recommendations for the acceptance testing, commissioning, and routine QA of low-energy electron UHDR linear accelerators. The proposed framework is not limited to any specific unit, making it applicable to all existing eFLASH units in the market. Through practical insights and theoretical discourse, this document establishes a benchmark for the commissioning of UHDR devices for clinical use.

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation.

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

Dynamics of synaptic damage in severe traumatic brain injury revealed by cerebrospinal fluid SNAP-25 and VILIP-1.

BACKGROUND: Biomarkers of neuronal, glial cells and inflammation in traumatic brain injury (TBI) are available but they do not specifically reflect the damage to synapses, which represent the bulk volume of the brain. Experimental models have demonstrated extensive involvement of synapses in acute TBI, but biomarkers of synaptic damage in human patients have not been explored. METHODS: Single-molecule array assays were used to measure synaptosomal-associated protein-25 (SNAP-25) and visinin-like protein 1 (VILIP-1) (along with neurofilament light chain (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillar acidic protein (GFAP), interleukin-6 (IL-6) and interleukin-8 (IL-8)) in ventricular cerebrospinal fluid (CSF) samples longitudinally acquired during the intensive care unit (ICU) stay of 42 patients with severe TBI or 22 uninjured controls. RESULTS: CSF levels of SNAP-25 and VILIP-1 are strongly elevated early after severe TBI and decline in the first few days. SNAP-25 and VILIP-1 correlate with inflammatory markers at two distinct timepoints (around D1 and then again at D5) in follow-up. SNAP-25 and VILIP-1 on the day-of-injury have better sensitivity and specificity for unfavourable outcome at 6 months than NFL, UCH-L1 or GFAP. Later elevation of SNAP-25 was associated with poorer outcome. CONCLUSION: Synaptic damage markers are acutely elevated in severe TBI and predict long-term outcomes, as well as, or better than, markers of neuroaxonal injury. Synaptic damage correlates with initial injury and with a later phase of secondary inflammatory injury.

Navigating the Critical Translational Questions for Implementing FLASH in the Clinic.

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of experimentation required to move forward in safe and decisive clinical trials. Here we review the available preclinical data pertaining to these questions and how they may inform strategies for FLASH cancer therapy clinical trials.

Categorization of the amyotrophic lateral sclerosis population via the clinical determinant of post-onset ΔFS for study design and medical practice.

The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS-R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS-R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS-R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post-onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post-onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post-onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design.

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization.

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 versus 10.2 × 106/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract.

Background: The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited. Purpose: We sought to evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP). Methods: C57BL/6J mice were subjected to total abdominal irradiation (11-14 Gy single fraction) under conventional irradiation (low DPP and low MDR, CONV) and various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. The effects of DPP were evaluated for DPPs of 1-6 Gy while the total dose and MDR were kept constant; the effects of MDR were evaluated for the range 0.3- 1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay. Results: Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to better sparing of regenerating crypts, with a more prominent effect seen at 12 and 14 Gy TAI. However, at fixed DPPs >4 Gy, similar sparing of crypts was demonstrated irrespective of MDR (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV for all MDRs from 0.3 Gy/s to 104 Gy/s, but at a lower DPP of 0.93 Gy, increasing MDR produced a greater survival effect. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model. Conclusions: This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Blood-CSF barrier integrity in amyotrophic lateral sclerosis.

The integrity of the blood-CSF barrier plays a major role in inflammation, but also in shielding the central nervous system from external and systemic - potentially toxic - factors. Here we report results of measurements of the albumin quotient - which is thought to mirror the integrity of the blood/CSF barrier - in 1059 amyotrophic lateral sclerosis patients. The results were compared with groups of patients suffering from Alzheimer´s disease, facial palsy and tension headache. The albumin quotient, an accepted measure of the blood/CSF barrier integrity, was not significantly different from control populations. In addition, we found that the albumin quotient correlated with survival of the patients; this effect was mainly driven by male patients and influenced by age, BMI and diabetes mellitus. We conclude that the blood/CSF barrier is intact in this large cohort of ALS patients and that the albumin quotient correlates with survival. Whether this is important for the pathogenesis of the disease, requires mechanistic studies.

Using Objective and Subjective Measures of Cognition to Predict Instrumental Activities of Daily Living Abilities in Multiple Sclerosis.

BACKGROUND: Cognitive impairment, difficulty performing basic activities of daily living (ADLs) and instrumental ADLs (IADLs), depression, and fatigue are common among individuals with multiple sclerosis (MS). Some associations between these symptoms are known; however, many of their relationships remain unclear. This study investigated the contributions of subjective and objective cognition, depressive symptom severity, and fatigue on ADLs and IADLs. METHODS: Participants (N = 217) were individuals with MS from a comprehensive MS center, participating in a larger study characterizing upper extremity function in MS. Outcome measures of ADL and IADL abilities were the Functional Status Index-Assistance (FSI-A) and Functional Status Index-Difficulty (FSI-D) and the Test D'évaluation Des Membres Supérieurs de Personnes Âgées (TEMPA). Predictors were objective cognition (Symbol Digit Modalities Test; SDMT), subjective cognition (Performance Scales©-Cognition; PS-C), depressive symptom severity (Center for Epidemiologic Studies Depression Scale; CES-D-10), and fatigue (Modified Fatigue Impact Scale; MFIS-5). Correlations were conducted, followed by hierarchal linear regressions. The SDMT and PS-C were entered into separate models. RESULTS: After controlling for demographics, the SDMT significantly predicted the TEMPA and FSI-A, while the PS-C predicted only the FSI-D. The CES-D-10 predicted the FSI-D even after accounting for PS-C and SDMT, while the MFIS-5 only predicted the FSI-D when the SDMT was included. Neither the CES-D-10 nor MFIS-5 significantly predicted the FSI-A or TEMPA. CONCLUSIONS: The way an individual with MS perceived their symptoms significantly contributed to their reported difficulty with functional tasks, while only their objective cognitive functioning predicted ADL and IADL performance and the level of assistance they would require.

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

Same-Day Primary Care Referral Versus Usual Care for Patients With Elevated Blood Pressures Seen in a Preoperative Clinic.

Background While several studies have suggested that anesthesia and surgical care episodes provide an opportunity to improve the diagnosis and treatment of hypertension, few studies have implemented and tested pragmatic care coordination efforts for this population. The present study aimed to examine the effects of same-day primary care referral vs. usual care on outpatient hypertension treatment among patients with elevated preoperative clinic blood pressure (BP). Methodology With institutional review board approval of the project as a quality improvement (QI) initiative not requiring consent, we conducted a prospective QI project comparing same-day preoperative primary care referral vs. usual care within comparable cohorts of US Veterans presenting to a preoperative evaluation clinic with elevated BP for whom treatment assignment was based on prior primary care clinic affiliation. Outpatient BP, antihypertensive medications, and antihypertensive dosages at the initial visit and for one year after the initial preoperative clinic visit were followed in the electronic health record. Results Between June 1, 2018, and June 1, 2019, one of the two on-site primary care groups (Firm A) at our facility agreed to accommodate same-day BP referrals. Patients in the second primary care group received standard preoperative care (Firm B). Charts for the pseudo-randomized cohort of Firm A and B patients were compared after 12 months to assess for changes in BP and hypertension treatment. Firm A and B patients were similar in demographics. Overall, 68 (91%) Firm A patients were correctly referred for primary care appointments. Moreover, 28 of 68 (41.2%) patients adhered to the same-day referral recommendation, with the remainder declining to attend the primary care visit. BPs were similar between Firm A and Firm B groups at 3, 6, 9, and 12 months post-intervention. Firm A adherent patients (i.e., those attending the referral) received hypertension treatment intensification sooner than Firm A non-adherent and Firm B patients (median (interquartile range) days to intensification = 21 (0.5-103.5) vs. 154 (45.5-239) and 170 (48-220), respectively; p = 0.038 and p = 0.048, respectively). Conclusions Our protocol achieved a high degree of same-day primary care referral (91%) in hypertensive patients presenting at the preoperative clinic. Although this limited study did not demonstrate improved BP control in patients who received same-day primary care, this group did show increased rates of rapid treatment intensification which may infer improved long-term health outcomes. Further work examining logistical barriers to patients attending same-day referrals is warranted.

Periodic motions with impact chatters in an impact Duffing oscillator.

The periodic motions of discontinuous nonlinear dynamical systems are very difficult problems to solve in engineering and physics. Until now, except for numerical studies, one cannot find a better way to solve such problems. In fact, one still has difficulty obtaining periodic motions in continuous nonlinear dynamical systems. In this paper, a method is presented systematically for periodic motions in discontinuous nonlinear dynamical systems. The stability and grazing bifurcations of such periodic motions are studied. Such a method is presented through discussion on a periodically forced, impact Duffing oscillator. Thus, periodic motions with impact chatters in a periodically forced Duffing oscillator with one-sidewall constraint are studied. The analytical conditions for motion grazing at the boundary are developed from discontinuous dynamical systems. The impact Duffing oscillator is discretized to generate subimplicit mappings. With impact, the mapping structures are employed to construct specific impact periodic motions for an impact Duffing oscillator. The bifurcation trees of impact chatter periodic motions are achieved semi-analytically. The grazing and period-doubling bifurcations are obtained, and the grazing bifurcations are for the appearing and disappearance for an impact chatter periodic motion. The impact chatter periodic motions with and without grazing are presented for illustration of impact periodic motion complexity in the impact Duffing oscillator.

Pediatric dermatologists versus AI bots: Evaluating the medical knowledge and diagnostic capabilities of ChatGPT.

This study evaluates the clinical accuracy of OpenAI's ChatGPT in pediatric dermatology by comparing its responses on multiple-choice and case-based questions to those of pediatric dermatologists. ChatGPT's versions 3.5 and 4.0 were tested against questions from the American Board of Dermatology and the "Photoquiz" section of Pediatric Dermatology. Results show that human pediatric dermatology clinicians generally outperformed both ChatGPT iterations, though ChatGPT-4.0 demonstrated comparable performance in some areas. The study highlights the potential of AI tools in aiding clinicians with medical knowledge and decision-making, while also emphasizing the need for continual advancements and clinician oversight in using such technologies.

Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.

Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer.

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.