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Abstract Gaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β‐glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G>C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill‐defined. We present a 20‐year‐old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols.

Abstract Impedance aggregometry is an alternative to light transmission aggregometry that allows analysis of platelet function in whole blood samples. We hypothesized (1) impedance aggregometry would produce repeatable results, (2) inhibition of cyclooxygenase with aspirin would attenuate aggregation responses to collagen and abolish the aggregation response to arachidonic acid (AA), and (3) thromboxane receptor antagonism (terutroban) would attenuate the aggregation response to AA. Venous blood was obtained from 11 participants three times separated by at least 2 weeks. One sample followed 7‐day‐aspirin intervention (81 mg once daily; ASA), the others no intervention (control). Aggregation was induced using 1 μg/mL collagen ([col 1]), 5 μg/mL collagen ([col 5]), and 50 mM AA via impedance aggregometry to determine total aggregation (AUC) analyzed for intra‐test repeatability, inter‐test repeatability, intervention (ASA or control), and incubation (saline or terutroban). [col 1] showed high intra‐test (p ≤ 0.03 visit 1 and 2) and inter‐test repeatability (p

Abstract Objectives Randomized controlled trials (RCTs) are the gold standard for evaluating the comparative efficacy and safety of new cancer therapies. However, enrolling patients in control arms of clinical trials can be challenging for rare cancers, particularly in the context of precision oncology and targeted therapies. External Control Arms (ECAs) are a potential solution to address these challenges in clinical research design. We conducted a scoping review to explore the use of ECAs in oncology. Methods We systematically searched four databases, namely MEDLINE, EMBASE, Web of Science, and Scopus. We screened titles, abstracts, and full texts for eligible articles focusing on patients undergoing therapy for cancer, employing ECAs, and reporting clinical outcomes. Results Of the 629 articles screened, 23 were included in this review. The earliest included studies were published in 1996, while most studies were published in the past 5 years. 44% (10/23) of ECAs were employed in blood‐related cancer studies. Geographically, 30% (7/23) of studies were conducted in the United States, 22% (5/23) in Japan, and 9% (2/23) in South Korea. The primary data sources used to construct the ECAs involved pooled data from previous trials (35%, 8/23), administrative health databases (17%, 4/23) and electronic medical records (17%, 4/23). While 52% (12/23) of the studies employed methods to align treatment and ECAs characteristics, 48% (11/23) lacked explicit strategies. Conclusion ECAs offer a valuable approach in oncology research, particularly when alternative designs are not feasible. However, careful methodological planning and detailed reporting are essential for meaningful and reliable results.

Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin‐28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B–lethal‐7 (let‐7; a microRNA that is a tumor suppressor)–lymphokine‐activated killer T‐cell‐originated protein kinase (PBK; also known as PDZ‐binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3‐MB‐patient‐derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N‐methyl‐N‐[3‐(3‐methyl‐1,2,4‐triazolo[4,3‐b]pyridazin‐6‐yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI‐TOPK‐032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B–let‐7–PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway.

Abstract Activation of the Simulator of Interferon Genes (STING) system by mitochondrial (mt) DNA can upregulate type 1 interferon genes and enhance immune responses to combat bacterial and viral infections. In cancers, the tumor‐derived DNA activates STING leading to upregulation of IFN‐beta and induction of antitumor T cells. The entire mtDNA from the cell lines was sequenced using next‐generation sequencing (NGS) technology with independent sequencing of both strands in both directions, allowing identification of low‐frequency heteroplasmy SNPs. There were 15 heteroplasmy SNPs showing a range from 3.4% to 40.5% occurrence in the K cybrid cell lines. Three H haplogroup cybrids possessed SNP heteroplasmy that ranged from 4.39% to 30.7%. The present study used qRT‐PCR to determine if cybrids of H and K haplogroups differentially regulate expression levels of five cancer genes (BRAC1, ALK, PD1, EGFR, and HER2) and seven STING subunits genes (CGAS, TBK1, IRF3, IκBa, NFκB, TRAF2, and TNFRSF19). Some cybrids underwent siRNA knockdown of STING followed by qRT‐PCR in order to determine the impact of STING on gene expression. Rho0 (lacking mtDNA) ARPE‐19 cells were used to determine if mtDNA is required for the expression of the cancer genes studied. Our results showed that (a) K cybrids have lower expression levels for BRAC1, ALK, PD1, EGFR, IRF3, and TNFRSF19 genes but increased transcription for IκBa and NFκB compared to H cybrids; (b) STING KD decreases expression of EGFR in both H and K cybrids, and (c) PD1 expression is negligible in Rho0 cells. Our findings suggest that the STING DNA sensing pathway may be a previously unrecognized pathway to target modulation of cancer‐related genes and the PD1 expression requires the presence of mtDNA.

Abstract The expressed goal of limiting workplace heat stress exposures to a core temperature (Tc) of 38°C traces back to a 1969 World Health Organization Technical Report (WHO Series 412). The actual goal was to limit exposures to the upper limit of the prescriptive zone (ULPZ). To explore the physiological strain at the ULPZ, progressive heat stress protocol data from Penn State University (PSU) and University of South Florida (USF) below and at the ULPZ were used to articulate the relation of Tc and heart rate (HR) to metabolic rate (MR) with consideration of acclimatization state, clothing, exposure condition (PreULPZ vs. ULPZ), and sex. Regression models demonstrated the association of MR and sex with Tc and HR. At the ULPZ, women had systematically higher values of Tc and HR than men at the same MR likely due to higher relative demands. There was no effect for acclimatization state and clothing. As expected for individuals, Tc was practically constant below the ULPZ and HR exhibited increasing values approaching the ULPZ. At 490 W, the high MR cited in the WHO document, the mean Tc for men was near the 38°C limit with systematically lower Tc at lower MRs.

Abstract We tested the hypothesis that post‐COVID‐19 adults (PC) would have impaired cutaneous nitric oxide (NO)‐mediated vasodilation compared to controls (CON). We performed a cross‐sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post‐diagnosis). COVID‐19 symptoms severity (survey) was assessed (0–100 scale for 18 common symptoms). NO‐dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG‐nitro‐L‐arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser‐Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax, p = 0.77) and NO‐dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO‐dependent vasodilation (r

Abstract Background Increased concentration of haptoglobin (Hp) in serum is associated with survival of critically ill humans and horses. High serum activity of liver‐derived enzyme is associated with sepsis in children and foals. Hypothesis/Objectives Investigate whether admission serum Hp and glutamic dehydrogenase (GLDH) are associated with systemic inflammatory response syndrome (SIRS) and survival of sick calves. Animals One hundred two calves. Methods Retrospective cross‐sectional study. Electronic medical records from all calves 140 bpm (HzR: 3.59, 95% CI: 1.05‐12.33), neutrophil count

Background Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate

Background In light of evidence from recent trials that endovascular thrombectomy (EVT) alone may potentially be noninferior to combined treatment, that is, with intravenous thrombolysis (IVT) with alteplase and EVT, we sought to understand physician and patient preferences around this issue. Methods We conducted a 2‐stage mixed methods study that included a structured, international, web‐based cross‐sectional survey among stroke physicians, and a focus group involving stroke survivors and caregivers. Demographic information was collected from all participants. The survey offered multiple choice questions and options to respond via free text which was analyzed quantitatively. The focus group was conducted online and analyzed qualitatively using a grounded theory approach. Results A total of 225 physicians (67% men) from 44 countries completed the survey. Most participants (70%) were between 31 and 50 years of age. Survey results showed that in current practice, 90% respondents would offer IVT to patients with large vessel occlusion stroke eligible for both IVT and EVT. When asked if their practice would change in light of recent trials, 63% responded no. When asked about the appropriate timing for IVT in the setting of large vessel occlusion stroke with EVT availability, 56% preferred to administer IVT immediately, 21% were willing to defer the decision for 30 minutes from groin puncture, and 8% were willing to defer for 60 minutes from groin puncture to assess if reperfusion was achieved with EVT. A total of 61% participants would choose to use tenecteplase over alteplase as the preferred drug for IVT if both drugs are backed by evidence. The focus group identified a need to better understand patient characteristics that may benefit from EVT‐only or combined strategies. The focus group also identified the need for more data to inform physician decision making. Conclusions Most physicians surveyed prefer IVT before EVT in patients with acute ischemic stroke attributable to large vessel occlusion, although there was some uncertainty around this issue. The need for further studies, including data on IVT with tenecteplase and among various patient subgroups to inform decision making, was apparent from both the survey and the patient focus group.

Abstract This case discusses a patient who presented with immune thrombocytopenia purpura (ITP) one week after COVID‐19 vaccination, introducing ITP as a consideration for a potential, but rare, adverse reaction to COVID‐19 vaccination.

Abstract Objective Eating difficulties coupled with cardiorespiratory spells delay acquisition of feeding milestones in convalescing neonates, and the mechanisms are unclear. Aims were to examine and compare the pharyngoesophageal–cardiorespiratory (PECR) response characteristics: (a) in control neonates and those with recurrent bradycardia spells; and (b) during pharyngeal stimulation when bradycardia occurs versus when no bradycardia occurs. Methods Preterm infants (N = 40, 27 ± 3 weeks gestation), underwent concurrent pharyngoesophageal manometry, electrocardiography, respiratory inductance plethysmography, and nasal airflow thermistor to evaluate pharyngoesophageal motility, heart rate (HR), and respiration during graded abrupt pharyngeal sterile water stimuli. Infants with recurrent bradycardia (N = 28) and controls (N = 12) were evaluated at 38 (38–40) and 39 (38–40) weeks postmenstrual age, respectively. Comparisons were performed (a) between study and control groups; and (b) among HR responses of 100 BPM. Results Overall, characteristics of PECR responses in infants with a history of recurrent bradycardia (vs. controls) did not differ (p > .05). However, when pharyngeal stimulus induced severe bradycardia (

Background Mitochondrial transplantation has been recently explored for treatment of very ill cardiac patients. However, little is known about the intracellular consequences of mitochondrial transplantation. This study aims to assess the bioenergetics consequences of mitochondrial transplantation into normal cardiomyocytes in the short and long term. Methods and Results We first established the feasibility of autologous, non‐autologous, and interspecies mitochondrial transplantation. Then we quantitated the bioenergetics consequences of non‐autologous mitochondrial transplantation into cardiomyocytes up to 28 days using a Seahorse Extracellular Flux Analyzer. Compared with the control, we observed a statistically significant improvement in basal respiration and ATP production 2‐day post‐transplantation, accompanied by an increase in maximal respiration and spare respiratory capacity, although not statistically significantly. However, these initial improvements were short‐lived and the bioenergetics advantages return to the baseline level in subsequent time points. Conclusions This study, for the first time, shows that transplantation of non‐autologous mitochondria from healthy skeletal muscle cells into normal cardiomyocytes leads to short‐term improvement of bioenergetics indicating “supercharged” state. However, over time these improved effects disappear, which suggests transplantation of mitochondria may have a potential application in settings where there is an acute stress.