Low Dose Research Articles

Association between treatment response and dose of blonanserin transdermal patch in patients with acute schizophrenia: A post hoc cluster analysis based on baseline psychiatric symptoms.

To explore the optimal dose of blonanserin transdermal patch (BNS-P) based on baseline psychiatric symptomatic characteristics during acute schizophrenia. A post hoc cluster analysis was conducted using data from a 6-week randomized, double-blind, placebo-controlled study of BNS-P (40 or 80 mg/day) in acute schizophrenia. We classified patients into three clusters based on baseline psychiatric symptoms. Efficacy was assessed using the change from baseline to week 6 in the PANSS total score. Safety was assessed by the incidence of adverse events. Among 577 patients, three clusters were identified, characterized by severe psychiatric (Cluster-S; n = 122), predominant negative (Cluster-N; n = 191), and predominant positive (Cluster-P; n = 264) symptoms. In Cluster-P, both BNS-P 40 and 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.036, effect size = 0.342; p < 0.001, effect size = 0.687, respectively). In Cluster-S and -N, only BNS-P 80 mg/day reduced PANSS total score significantly more than placebo (p = 0.045, effect size = 0.497; p = 0.034, effect size = 0.393, respectively). The effect size was greater at 80 mg/day than at 40 mg/day across all clusters. The most common treatment-emergent adverse events were akathisia and skin-related adverse events in all clusters. BNS-P exhibited a dose-dependent antipsychotic effect in all clusters, particularly highlighting its efficacy in patients with predominant positive symptoms, even at lower doses. These findings provide novel and valuable insights for determining BNS-P dose tailoring to individual symptomatic characteristics in real-world practice.

Higher dose antiviral therapy for herpes infections is associated with a risk of serious adverse events in older adults with chronic kidney disease.

Antiviral use has been linked to encephalopathy and elevated serum creatinine concentrations in individuals with chronic kidney disease (CKD) in case reports. Using linked healthcare data in Ontario, we conducted a population-based cohort study on adults aged ≥66 years not receiving dialysis and newly prescribed oral acyclovir, valacyclovir, or famciclovir in the outpatient setting (2008-2022) at higher versus lower doses. The primary composite outcome, a hospital visit with encephalopathy or acute kidney injury (AKI) within 14 days of initiating antiviral treatment, was examined in a primary cohort. AKI was assessed in a secondary cohort of older adults with CKD with available linked hospital-based laboratory (lab) data. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson and binomial regression. In the primary cohort, higher- versus lower-dose antiviral was not associated with an increased 14-day risk of hospital visit with encephalopathy or AKI. However, Higher- versus lower-dose antiviral was associated with a higher risk of a hospital visit with AKI when assessed using lab values (weighted number of events, 70 of 8407 [0.83%] versus 18 of 8230 [0.22%], respectively; weighted RR, 3.83 [95% CI, 1.87-7.87]; weighted RD, 0.62% [95% CI, 0.37%-0.86%]). In older adults with CKD, starting an antiviral at a higher versus lower dose was associated with a higher risk of AKI, although the absolute risk of this event was <1%.

Suppression of Aseptic Inflammation Reduces the Severity of Remodeling of the Pulmonary Artery Branches and Improves Progressing of Experimental Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism, characterized by increased pressure in the pulmonary artery and impaired lysis of thromboemboli. Previously, the presence of aseptic inflammation in CTEPH was identified in the wall of the pulmonary artery branches and perivascularly. However, the role of this inflammation in the CTEPH formation is unknown. The aim of the work was to study the effect of aseptic inflammation on the CTEPH formation and progression. The experiments were performed on 54 male rats. The CTEPH model was reproduced by repeated intravenous administration of partially biodegradable microspheres (MS). Immediately after the last administration of MS, all animals were divided into groups: control CTEPH (c.CTEPH) – saline solution was administered intramuscularly (i/m) for 6 weeks; low dose of prednisolone (LD) – prednisolone was administered i/m at a dose of 1.5 mg/kg; high dose (HD) – prednisolone was administered i/m at a dose of 6 mg/kg; healthy animals. After 6 weeks, the following was performed: treadmill test, TTE, cardiac catheterization with manometry, and histological examination of the lungs. In a separate series of experiments, the severity of inflammatory infiltration of the vascular wall and perivascular zone was assessed by immunohistochemical studies (IHC). In the LD group, there was the decreasing of hypertrophy index (HI) and the percentage of collagen fibers in the vascular wall compared to c.CTEPH. There was a significantly greater reduction in HI compared to HD. In the HD group, there was positive effect on the percentage of collagen fibers in the vascular wall, this parameter did not significantly differ from healthy animals. According to IHC data, prednisolone in low dose effectively suppressed inflammatory infiltration of the vascular wall and perivascular space. The results of the study revealed the ability of prednisolone, by suppressing aseptic inflammation, to reduce the severity of remodeling of the pulmonary artery branches.

O-GlcNAcylation inhibition redirects the response of colon cancer cells to chemotherapy from senescence to apoptosis.

The potential use of pro-senescence therapies, known as TIS (Therapy-Induced Senescence), for the treatment of colorectal cancer (CRC) generated significant interest since they require lower doses compared to those required for inducing apoptosis. However, the senescent cell cycle-arrested cancer cells are long-lived, and studies have revealed escape mechanisms contributing to tumor recurrence. To deepen our understanding of the survival pathways used by senescent cancer cells, we delved into the potential involvement of the hexosamine biosynthetic pathway (HBP). HBP provides UDP-GlcNAc, the substrate for O-GlcNAc transferase (OGT), which catalyzes O-GlcNAcylation, a post-translational modification implicated in regulating numerous cellular functions and aberrantly elevated in CRC. In this study, we demonstrated, in the p53-proficient colon cancer cell lines HCT116 and LS174T, that TIS induced by low-dose SN38 or etoposide treatment was accompanied with a decrease of GFAT (the rate limiting enzyme of the HBP), OGT and O-GlcNAcase (OGA) expression correlated with a slight reduction in O-GlcNAcylation levels. Further decreasing this level of O-GlcNAcylation by knocking-down GFAT or OGT redirected the cellular response to subtoxic chemotherapy doses from senescence to apoptosis, in correlation with an enhancement of DNA damages. Pharmacological inhibition of OGT with OSMI-4 in HCT116 and LS174T cells and in a patient-derived colon tumoroid model supported these findings. Taken together, these results suggest that combing O-GlcNAcylation inhibitors to low doses of conventional chemotherapeutic drugs could potentially reduce treatment side effects while preserving efficacy. Furthermore, this approach may increase treatment specificity, as CRC cells exhibit higher O-GlcNAcylation levels compared to normal tissues.

The Design of Novel 3D-Printed, Moulded, and Oral Viscous Budesonide Formulations for Paediatrics: A Comparative Evaluation of Their Mucoadhesive Properties.

Paediatric eosinophilic oesophagitis (EoE) treatment is challenging due to the limited number of age-appropriate formulations. This study aims to develop and evaluate oral viscous suspensions and solid formulations of budesonide (BUD), focusing on their in vitro mucoadhesive properties, to enhance drug delivery and therapeutic outcomes in paediatric EoE. This study encompasses the development of oral viscous suspensions and orodispersible solid formulations (moulded tablets and 3D-printed dosage forms) containing BUD. The formulations underwent quality control tests as per the European Pharmacopoeia, chemical stability assessments, and an in vitro evaluation of their mucoadhesiveness properties. A validated analytical method enabled accurate BUD quantification and efficient extraction, and all developed formulations demonstrated chemical stability for 30 days, meeting Ph. Eur. quality standards. Three-dimensional printing using SSE successfully produced 1 mg and 0.5 mg BUD printlets, complying with quality tests for conventional tablets. Formulations containing xanthan gum (L2-XG and P1-0.5-XG) exhibited superior mucoadhesive properties. L2-XG showed significantly higher mucoadhesion than L1-MC. Among the solid formulations, P1-0.5-XG demonstrated the highest mucoadhesive properties. This is the first study to develop solid oral dosage forms of BUD at a very low dose, specifically for paediatric use. The results highlight the potential of 3D printing for developing individualised orodispersible BUD formulations with improved bioadhesion for paediatric EoE treatment. The L2-XG formulation and the XG-containing printlets are the most promising formulations in terms of increasing contact time with the oesophageal mucosa, which could translate into improved therapeutic efficacy in this patient population.

Long-term exposure to environmentally relevant Bisphenol-A levels affects growth, swimming, condition factor, sex ratio and histology of juvenile zebrafish

Bisphenol A (BPA) is an environmental estrogen which perturbs hormone signaling pathways adversely affecting aquatic organisms. To evaluate the impact of developmental exposure to long term yet environmentally relevant low doses of BPA, wild-type juvenile zebrafish of 35 days post fertilization were treated with BPA (1 and 10 µg/L), treatment control (0.5% v/v methanol) and control for 60 days. Both BPA treatments led to significantly increased morality overtime. Length increment and specific growth rates became significantly high in BPA exposed zebrafish overtime. Obesogenic property of BPA was not evident with longexposure to low BPA doses. A significantly high and BPA dose-dependent female-biased sex ratios were observed following the juvenile exposure. Significantly low swimming speed was recorded in the fish of both BPA-treated tanks than that of control. Condition factor was significantly low in BPA exposed fish indicating the poor-wellness. There were numerous histopathological alterations of gonads, liver and kidney indicating impacts of juvenile exposure in zebrafish. Altered growth, swimming, mortality, feminization and histopathological changes in zebrafish induced by BPA indicate the risks associated with developmental exposures. The findings call for more comprehensive studies to comprehend the ecological risks imposed by low concentrations of environmental estrogens in urban aquatic ecosystems.

Detection of seizure clustering using ultralong-term subcutaneous EEG monitoring

AbstractEpileptic seizures usually occur unpredictably yet not necessarily at random times. Cyclical patterns of seizure recurrence have been broadly described. Long-term seizure documentation may reveal individual cyclical seizure patterns; however, seizure reporting by patients or their caregivers is often inaccurate. Modern technologies for at-home monitoring of epileptic seizures enable continuous EEG recording for objective seizure counts over long-term timescales. Here, we present the clinical case of a patient with temporal lobe epilepsy due to hippocampal sclerosis who underwent ultralong-term subcutaneous EEG recording over a 1-year period, which revealed the occurrence of seizure clusters at three- to four-weekly intervals. The case demonstrates the possibility of detection of subject-specific seizure timing using a minimally invasive subcutaneous EEG recorder for ultralong-term at-home seizure monitoring. Information about individual seizure timing may contribute to a more personalized chronotherapeutic treatment approach in which antiseizure medication can be maintained at low doses during the low-risk periods and increased briefly before the anticipated seizures.

Exploratory analysis of agro-morphological characteristics in Nigella sativa L. plant genotypes to determine mutagen colchicine ameliorative/ non-ameliorative impacts.

This experimental study aimed to elucidate the optimal colchicine concentration for inducing polyploidy and to examine the morphological effects on Nigella sativa L. (family Ranunculaceae) plants recognized as 'Kalonji' in India. Here, seeds were exposed with different concentration of colchicine ranging from 0.025 to 0.4% with varying time duration (24-48h). The agro-morphological attributes and chromosome counts of the putative polyploids were compared with control diploid plants, revealing significant differences. The ploidy level determined by chromosome counts revealed that 0.05-0.1% concentration of colchicine induced tetraploids within both plant genotypes for 24h and 48h. However, results based on agro-morphological trait correlation analysis revealed more significant association among yield traits at 0.1% concentration and the principal component analysis revealed that the maximum possible ameliorative effect of the colchicine dose was the lowest concentration (0.025% for a 48-hour exposure time) for the AN1 genotype; likewise, a 0.05% concentration established a more positive association in terms of growth and yield attributes for the AN20 genotype. This study demonstrated that low dosages (0.025% and 0.1%) strongly impact plant growth and yield, whereas higher dosages obliterate these positive effects and add destructive characteristics within plants which ultimately reduces yield.

Gadolinium-based coronary CT angiography on a clinical photon-counting-detector system: a dynamic circulating phantom study

BackgroundCoronary computed tomography angiography (CCTA) offers non-invasive diagnostics of the coronary arteries. Vessel evaluation requires the administration of intravenous contrast. The purpose of this study was to evaluate the utility of gadolinium-based contrast agent (GBCA) as an alternative to iodinated contrast for CCTA on a first-generation clinical dual-source photon-counting-detector (PCD)-CT system.MethodsA dynamic circulating phantom containing a three-dimensional-printed model of the thoracic aorta and the coronary arteries were used to evaluate injection protocols using gadopentetate dimeglumine at 50%, 100%, 150%, and 200% of the maximum approved clinical dose (0.3 mmol/kg). Virtual monoenergetic image (VMI) reconstructions ranging from 40 keV to 100 keV with 5 keV increments were generated on a PCD-CT. Contrast-to-noise ratio (CNR) was calculated from attenuations measured in the aorta and coronary arteries and noise measured in the background tissue. Attenuation of at least 350 HU was deemed as diagnostic.ResultsThe highest coronary attenuation (441 ± 23 HU, mean ± standard deviation) and CNR (29.5 ± 1.5) was achieved at 40 keV and at the highest GBCA dose (200%). There was a systematic decline of attenuation and CNR with higher keV reconstructions and lower GBCA doses. Only reconstructions at 40 and 45 keV at 200% and 40 keV at 150% GBCA dose demonstrated sufficient attenuation above 350 HU.ConclusionCurrent PCD-CT protocols and settings are unsuitable for the use of GBCA for CCTA at clinically approved doses. Future advances to the PCD-CT system including a 4-threshold mode, as well as multi-material decomposition may add new opportunities for k-edge imaging of GBCA.Relevance statementPatients allergic to iodine-based contrast media and the future of multicontrast CT examinations would benefit greatly from alternative contrast media, but the utility of GBCA for coronary photon-counting-dector-CT angiography remains limited without further optimization of protocols and scanner settings.Key PointsGBCA-enhanced coronary PCD-CT angiography is not feasible at clinically approved doses.GBCAs have potential applications for the visualization of larger vessels, such as the aorta, on PCD-CT angiography.Higher GBCA doses and lower keV reconstructions achieved higher attenuation values and CNR.Graphical

Changes in Auditory Performance Following a Virtual Reality Music Concert.

The purpose of this study was to evaluate threshold and suprathreshold auditory risk from a newly popular platform of music concert entertainment; virtual reality (VR) headsets. Recreational noise exposure to music is the primary source of hearing hazard in young-adults, with noise doses of in-person concert venues and music festivals well in excess of the recommended daily exposure recommendation from the National Institute for Occupational Safety and Health. While research on the relationship between personal music players and noise-induced hearing loss risk is abundant, no study has yet evaluated noise-induced hearing loss risk from VR headsets, which are newest to the commercial market at this time. Thirty-one young-adult participants (18 to 25 years) with normal-hearing sensitivity (0 to 16 dB HL) experienced a VR music concert and participated in three data collection timepoints: Session A preexposure, Session A post-exposure, and Session B post-exposure. Participants underwent baseline testing for audiometry (0.25 to 20 kHz), distortion product otoacoustic emission testing (1 to 10 kHz), and Words-in-Noise testing. Participants then wore a commercially available VR headset (Meta Quest 2) and experienced a freely available online VR music concert (via the video-sharing website "YouTube"). The VR music concert duration was 90 min set to maximum volume, which yielded an average sound level equivalent of 78.7 dBA, max sound level of 88.2 dBA, and LC peak sound level of 98.6 dBA. Post-exposure testing was conducted immediately at the conclusion of the VR concert, and again within 24 hr to 1 week after the exposure. Participants also answered a questionnaire that estimated noise exposure history (National Acoustics Laboratory "Noise Calculator"). Post-exposure deficit was not observed in DPOAEs or Words-in-Noise score (p's > 0.05). However, statistically significant temporary post-exposure deficit was observed in audiometry at 4, 8, and 12.5 kHz (p's < 0.05) (mean differences: 2 to 3 dB HL). Twenty-four hours and 1-week post-exposure measurements revealed no permanent changes from baseline measurements (p's > 0.05) aside from one spurious difference at 12.5 kHz. Males tended to exhibit a significantly higher noise history score on average than females. The primary, secondary, and tertiary sources of noise hazard history in this young-adult cohort included amplified music. These preliminary data suggest that VR music concerts-which are likely to produce a substantially lower noise dose than in-person music concerts-may still be capable of producing at least slight, temporary threshold shifts on the order of 2 to 3 dB HL. Future research should include VR headsets in personal music player risk assessment, as the VR music concert platform is increasing rapidly in popularity among young-adults.

Gladiolin produced by pathogenic Burkholderia synergizes with amphotericin B through membrane lipid rearrangements.

Amphotericin B (AmpB) is one of the oldest antifungal drugs in clinical use. It is an effective therapeutic, but it comes with toxicity issues due to the similarities between its fungal target (the membrane lipid ergosterol) and its mammalian counterpart (cholesterol). One strategy to improve its activity/toxicity relationship is by combinatorial therapy with potentiators, which would enable a lower therapeutic dose of AmpB. Here, we report on the discovery of the antibiotic gladiolin as a potentiator of AmpB against several priority human fungal pathogens and fungal biofilms, with no increased toxicity against mammalian cells. We show that gladiolin potentiates AmpB by increasing and accelerating membrane damage. Our findings also provide insights into the on-going debate about the mechanism of action of AmpB by indicating that both proposed mechanisms, extraction of ergosterol from membranes and pore formation, are potentiated by gladiolin.

Enhancing Bone Formation Through bFGF-Loaded Mesenchymal Stromal Cell Spheroids During Fracture Healing in Mice.

This study aimed to evaluate the osteogenic potential of mesenchymal stromal cell (MSC) spheroids combined with the basic fibroblast growth factor (bFGF) in a mouse femur fracture model. To begin, MSC spheroids were generated, and the expression of key trophic factors (bFGF Bmp2, and Vegfa) was assessed using quantitative PCR (qPCR). A binding assay confirmed the interaction between the bFGF and the spheroids' extracellular matrix. The spheroid cultures significantly upregulated bFGF, Bmp2, and Vegfa expression compared to the monolayers (p < 0.001), and the binding assay demonstrated effective bFGF binding to the MSC spheroids. Following these in vitro assessments, the mice were divided into five groups for the in vivo study: (1) no treatment (control), (2) spheroids alone, (3) bFGF alone, (4) bFGF-loaded spheroids (bFGF-spheroids), and (5) non-viable (frozen) bFGF-loaded spheroids (bFGF-dSpheroids). Bone formation was analyzed by a micro-CT, measuring the bone volume (BV) and bone mineral content (BMC) of the mice four weeks post-fracture. A high dose of the bFGF (10 µg) significantly promoted bone formation regardless of the presence of spheroids, as evidenced by the increases in BV (bFGF, p = 0.010; bFGF-spheroids, p = 0.006; bFGF-dSpheroids, p = 0.032) and BMC (bFGF, p = 0.023; bFGF-spheroids, p = 0.004; bFGF-dSpheroids, p = 0.014), compared to the controls. In contrast, a low dose of the bFGF (1 µg) combined with the MSC spheroids significantly increased BV and BMC compared to the control (BV, p = 0.012; BMC, p = 0.015), bFGF alone (BV, p = 0.012; BMC, p = 0.008), and spheroid (BV, p < 0.001; BMC, p < 0.001) groups. A low dose of the bFGF alone did not significantly promote bone formation (p > 0.05). The non-viable (frozen) spheroids loaded with a low dose of the bFGF resulted in a higher BV and BMC compared to the spheroids alone (BV, p = 0.003; BMC, p = 0.017), though the effect was less pronounced than in the viable spheroids. These findings demonstrate the synergistic effect of the bFGF and MSC spheroids on bone regeneration. The increased expression of the BMP-2 and VEGF observed in the initial experiments, coupled with the enhanced bone formation in vivo, highlight the therapeutic potential of this combination. Future studies will aim to elucidate the underlying molecular mechanisms and assess the long-term outcomes for bone repair strategies.

Does hCG-trigger in the mild stimulation protocol for endometrial preparation have any effect on pregnancy outcome in frozen-thawed embryo transfer?

BackgroundRecent literature has explored the role of human chorionic gonadotropin (hCG) triggering in frozen embryo transfer (FET) cycles with natural endometrial preparation. Despite this, the impact of hCG triggering on pregnancy outcomes following endometrial preparation with mild stimulation (mST) using Letrozole and Gonadotropins remains inadequately characterized. This study aimed to elucidate the effects of hCG-trigger on pregnancy outcomes in mST-FET cycles.MethodsIn the present retrospective cohort study, the pregnancy outcomes of 409 eligible patients who underwent FET cycles with endometrial preparation using a mild ovarian stimulation protocol by letrozole plus low dose gonadotropins at the Royan Institute between 2020 and 2022, were investigated. The study population were segregated into two distinct groups according to type of ovulation: the spontaneous ovulation group (n = 138) and the hCG-trigger group (n = 271). The pregnancy outcomes including implantation and clinical pregnancy rates (CPR) and live birth rates (LBR) were compared between two groups. The multivariable logistic regression was performed to detect the most significant variables related to the LBR in the mST-FET cycles.ResultsDemographic and baseline characteristics were comparable between groups. No significant difference was found in terms of implantation rate (0.65 ± 0.32 vs. 0.60 ± 0.30, P-value: 0.31), CPR (37% vs. 39.7%, P-value: 0.53), and LBR (35.5% vs. 37.3%, P-value: 0.74) in the spontaneous ovulation and hCG-trigger groups, respectively. The logistic regression analysis revealed that only the stage of the transferred embryo exhibited a significant relationship with LBR (blastocyst vs. cleavage: odds ratio (OR); 2.33, 95% confidence interval (CI):1.41–3.86, P-value = 0.001).ConclusionPregnancy outcomes in the mST-FET cycles, including implantation rate, CPR, and LBR are comparable in cycles with or without hCG triggering. Based on the findings from multivariate regression analysis, the sole significant predictive factor for the LBR was the transfer of blastocyst embryos. It is recommended that these results be examined and discussed in future prospective studies with a larger sample size, considering the lack of comparable research in this field.

Effect of follicle-stimulating hormone dose on the risk of being classified as suboptimal responders according to the POSEIDON criteria.

The purpose of this study is to investigate the impact of daily follicle-stimulating-hormone (FSH) dose on the likelihood of suboptimal response to ovarian stimulation (OS) for in vitro fertilization (IVF) according to POSEIDON's criteria. A tri-center retrospective cohort study (2015-2017) including women with normal anti-Müllerian hormone (AMH ≥ 1.2ng/mL) and antral follicle count (AFC ≥ 5) values per POSEIDON's criteria, undergoing their first IVF/ICSI cycle using conventional OS (FSH ≥ 150IU/day). Suboptimal response was the retrieval of 4-9 oocytes. In previous research, we detected an AMH ≤ 2.97ng/mL and AFC ≤ 12 as the optimal cut-offs predicting suboptimal response. Therefore, we examined the effect of daily FSH dose (≤ 300IU versus > 300IU) on suboptimal response risk for each AMH and AFC value within these thresholds (AMH between 1.20 and 2.97ng/mL, by 0.01ng/mL increments; and an AFC between 5 and 12, by unit increments). Analysis involved contingency tables and multivariable logistic regression. Included were 4005 patients with AMH and AFC values in the specific range, among whom 2131 (53.2%) were suboptimal responders. Among 177 AMH groups analyzed, apart from three distributed irregularly, daily FSH doses > 300IU versus lower doses (≤ 300IU) did not decrease suboptimal response risk; similarly, higher doses did not decrease risk at the eight AFC values examined (p > 0.05 for all). Using multivariable logistic regression, FSH doses were not associated with suboptimal response risk. Conversely, female age, AMH, AFC, and gonadotropin type were associated with suboptimal response. In women with AMH values between 1.20 and 2.97ng/mL and/or AFC between 5 and 12, FSH dose increase did not decrease suboptimal response risk. Individualizing the gonadotropin regimen and considering LH activity supplementation to FSH may mitigate risks.

Risk-Stratified Radiotherapy in Pediatric Cancer

While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible for late toxicity. In the past decade, radiotherapy has been omitted in patients achieving excellent response to chemotherapy, such as in Hodgkin lymphoma and some Wilms tumors with lung metastases. Likewise, response to chemotherapy has been used to determine whether lower doses of radiation can be delivered in intracranial germinoma and pediatric nasopharyngeal carcinoma. Molecular subtyping in medulloblastoma is currently being employed, and in WNT-pathway M0 tumors, the reduction in radiotherapy dose to the craniospinal axis and tumor bed is currently being investigated. Finally, dose escalation was recently evaluated in patients with rhabdomyosarcoma &gt; 5 cm who do not achieve a complete response to initial 9 weeks of chemotherapy as well as for unresectable Ewing sarcoma patients to improve local control.

Low doses of ionising radiation: definitions and contexts

The term 'low dose' is applied to different levels of dose depending on the circumstances of exposure, with the potential for confusion unless the reasoning is clear. The United Nations Scientific Committee on the Effects of Ionising Radiation has defined low absorbed doses of ionising radiation as below about 100 mGy, and low dose rates as below 0.1 mGy min-1 (6 mGy h-1). These values relate to the interpretation of scientific evidence from epidemiological and biological studies. The International Commission on Radiological Protection has used similar values of 100 mSv and 5 mSv h-1 and applied this categorisation directly to the specific situation of patients undergoing diagnostic procedures: doses below 100 mSv were referred to as 'low' and doses below 10 mSv as 'very low'. Consideration of other exposure situations suggest that the same terms can be used for exposures received by emergency workers. However, for workers and members of the public in planned exposure situations, it is suggested that the term 'low dose' applies to doses below 10 mSv and 1 mSv, respectively - that is, below the dose limits. In each case, dose is being used as a surrogate for risk - risks at low doses are uncertain and estimates may change, but order of magnitude considerations are sufficient in most cases. Doses of < 100 mSv, < 10 mSv and < 1 mSv correspond to life-time cancer risk estimates of the order of < 10-2, < 10-3 and < 10-4, respectively.&#xD.

The Efficacy and Safety of Stepwise Oral Food Challenge in Children with Cow’s Milk Allergy

Plain Language SummaryStepwise oral food challenge (OFC) tests begin with low doses of allergens, progressing to full doses. This is one of the strategies used to avoid anaphylactic reactions to the reintroduction of allergens. We previously reported the safety and efficacy of hen egg OFC. In this study, we discuss it for cow’s milk (CM) allergy. We included 927 children (median age, 3.2 years) who underwent CM-OFC between 2017 and 2021. The target challenge dose was classified as low (<10 mL), middle (≥10 mL but <100 mL), or full. When the participants reacted to low doses, they underwent very low-dose OFC using baked milk or <1 mL of CM. Positive reactions developed in 210 cases (22.7%), including 69 anaphylactic reactions (7.4%). A lower target dose resulted in more positive OFC results and anaphylaxis. Multivariate analysis indicated that only in low-dose OFCs, higher CM-specific IgE (CM-sIgE) levels, younger age, and complete CM elimination were associated with positive OFC results. Food ladders, an approach to reintroduce allergens, are becoming increasingly popular. Although we believe that OFC is a safer strategy to reintroduce CM to children with CM allergy, our CM-OFCs appeared to develop more anaphylactic reactions than milk ladders. The stepwise OFC reintroduced small amounts of CM, even in cases with high CM-sIgE levels or a history of anaphylaxis. Performing CM-OFC at a younger age, preferably from infancy, with very low doses, similar to milk ladders, may facilitate the safe reintroduction of CM.

Evaluation of the Protective Efficacy of Different Doses of a Chlamydia abortus Subcellular Vaccine in a Pregnant Sheep Challenge Model for Ovine Enzootic Abortion.

Chlamydia abortus causes the disease ovine enzootic abortion, which is one of the most infectious causes of foetal death in small ruminants worldwide. While the disease can be controlled using live and inactivated commercial vaccines, there is scope for improvements in safety for both sheep and human handlers of the vaccines. We have previously reported the development of a new prototype vaccine based on a detergent-extracted outer membrane protein preparation of C. abortus that was determined to be more efficacious and safer than the commercial vaccines when administered in two inoculations three weeks apart. In this new study, we have developed this vaccine further by comparing its efficacy when delivered in one or two (1 × 20 µg and 2 × 10 µg) doses, as well as also comparing the effect of reducing the antigen content of the vaccine by 50% (2 × 5 µg and 1 × 10 µg). All vaccine formulations performed well in comparison to the unvaccinated challenge control group, with no significant differences observed between vaccine groups, demonstrating that the vaccine can be administered as a single inoculation and at a lower dose without compromising efficacy. Future studies should focus on further defining the optimal antigen dose to increase the commercial viability of the vaccine.

Straightforward Phase I Dose-Finding Design for Healthy Volunteers Accounting for Surrogate Activity Biomarkers

Conventionally, a first-in-human phase I trial in healthy volunteers aims to confirm the safety of a drug in humans. In such situations, volunteers should not suffer from any safety issues and simple algorithm-based dose-escalation schemes are often used. However, to avoid too many clinical trials in the future, it might be appealing to design these trials to accumulate information on the link between dose and efficacy/activity under strict safety constraints. Furthermore, an increasing number of molecules for which the increasing dose-activity curve reaches a plateau are emerging. In a phase I dose-finding trial context, our objective is to determine, under safety constraints, among a set of doses, the lowest dose whose probability of activity is closest to a given target. For this purpose, we propose a two-stage dose-finding design. The first stage is a typical algorithm dose escalation phase that can both check the safety of the doses and accumulate activity information. The second stage is a model-based dose-finding phase that involves selecting the best dose-activity model according to the plateau location. Our simulation study shows that our proposed method performs better than the common Bayesian logistic regression model in selecting the optimal dose.

Effect of Unfractionated Heparin Dose on Complement Activation and Selected Extracellular Vesicle Populations during Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) provides critical support for patients with severe cardiopulmonary dysfunction. Unfractionated heparin (UFH) is used for anticoagulation to maintain circuit patency and avoid thrombotic complications, but it increases the risk of bleeding. Extracellular vesicles (EVs), nano-sized subcellular spheres with potential pro-coagulant properties, are released during cellular stress and may serve as potential targets for monitoring anticoagulation, particularly in thromboinflammation. We investigated the impact of UFH dose during ECMO therapy at the coagulation-inflammation interface level, focusing on complement activation and changes in circulating large EV (lEV) subsets. In a post hoc analysis of a multicenter randomized controlled trial comparing two anticoagulation management algorithms, we examined lEV levels and complement activation in 23 veno-venous-ECMO patients stratified by UFH dose. Blood samples were collected at different time points and grouped into three phases of ECMO therapy: initiation (day 1), mid (days 3-4), and late (days 6-7). Immunoassays detected complement activation, and flow cytometry analyzed lEV populations with an emphasis on mitochondria-carrying subsets. Patients receiving <15 IU/kg/h UFH exhibited higher levels of the complement activation product C5a and soluble terminal complement complex (sC5b-9). Lower UFH doses were linked to increased endothelial-derived lEVs, while higher doses were associated with elevated RBC-derived and mitochondria-positive lEVs. Our findings suggest the potential theranostic relevance of EV detection at the coagulation-inflammation interface. Further research is needed to standardize EV detection methods and validate these findings in larger ECMO patient cohorts.