Predicting neural activity of whole body cast shadow through object cast shadow in dynamic environments.

Shadows, as all other objects that surround us, are incorporated into the body and extend the body mediating perceptual information. The current study investigates the hypothesis according to which the perception of object shadows would predict the perception of body shadows. 38 participants (19 males and 19 females) aged 23 years on average were immersed into a virtual reality environment and instructed to perceive and indicate the coincidence or non coincidence between the movement of a ball shadow with regard to ball movement on the one hand, and between their body shadow and their body position in space on the other. Their brain activity was recording via a 32-channel EEG system, in which beta (13.5-30 Hz) oscillations were analyzed. A series of Multiple Regression Analysis (MRA) revealed that the beta dynamic oscillations patterns of the bilateral occipito-parieto-frontal pathway associated with the perception of ball shadow appeared to be a significant predictor of the increase in beta oscillations across frontal areas related to the body shadow perception and the decrease in beta oscillations across frontal areas connected to the decision making of the body shadow. Taken together, the findings suggest that inferential thinking ability relative to body shadow would be reliably predicted from object shadows and that the bilateral beta oscillatory modulations would be indicative of the formation of predictive neural frontal assemblies, which encode and infer body shadow neural representation, that is, a substitution of the physical body.

Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans.

BACKGROUND: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment. PURPOSE: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques. MATERIALS AND METHODS: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM). RESULTS: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task. CONCLUSION: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information.

Survey of stigma across healthcare workers in an urban, academic medical center regarding perinatal patients using opioids.

BACKGROUND AND OBJECTIVES: To examine healthcare workers' attitudes towards pregnant woman using opioids across provider type, specialty, and years of service. METHODS: Cross-sectional, anonymous survey of healthcare workers at an urban, academic medical center regarding attitudes towards pregnant women using opioids. RESULTS: One hundred and nineteen surveys were completed. Nurses were less likely to feel sympathetic towards pregnant women that use opioids (p = .016). DISCUSSION AND CONCLUSIONS: Differences in attitudes towards pregnant women using opioids were found between clinicians and nurses. SCIENTIFIC SIGNIFICANCE: Training and experience may contribute to attitude differences towards pregnant women using opioids.

Trait profiles in difficult-to-treat asthma: Clinical impact and response to systematic assessment.

BACKGROUND: Multidisciplinary systematic assessment improves outcomes in difficult-to-treat asthma, but without clear response predictors. Using a treatable-traits framework, we stratified patients by trait profile, examining clinical impact and treatment responsiveness to systematic assessment. METHODS: We performed latent class analysis using 12 traits on difficult-to-treat asthma patients undergoing systematic assessment at our institution. We examined Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores, FEV1 , exacerbation frequency, and maintenance oral corticosteroid (mOCS) dose, at baseline and following systematic assessment. RESULTS: Among 241 patients, two airway-centric profiles were characterized by early-onset with allergic rhinitis (n = 46) and adult onset with eosinophilia/chronic rhinosinusitis (n = 60), respectively, with minimal comorbid or psychosocial traits; three non-airway-centric profiles exhibited either comorbid (obesity, vocal cord dysfunction, dysfunctional breathing) dominance (n = 51), psychosocial (anxiety, depression, smoking, unemployment) dominance (n = 72), or multi-domain impairment (n = 12). Compared to airway-centric profiles, non-airway-centric profiles had worse baseline ACQ-6 (2.7 vs. 2.2, p < .001) and AQLQ (3.8 vs. 4.5, p < .001) scores. Following systematic assessment, the cohort showed overall improvements across all outcomes. However, airway-centric profiles had more FEV1 improvement (5.6% vs. 2.2% predicted, p < .05) while non-airway-centric profiles trended to greater exacerbation reduction (1.7 vs. 1.0, p = .07); mOCS dose reduction was similar (3.1 mg vs. 3.5 mg, p = .782). CONCLUSION: Distinct trait profiles in difficult-to-treat asthma are associated with different clinical outcomes and treatment responsiveness to systematic assessment. These findings yield clinical and mechanistic insights into difficult-to-treat asthma, offer a conceptual framework to address disease heterogeneity, and highlight areas responsive to targeted intervention.

Asia-Inclusive Clinical Research and Development Enabled by Translational Science and Quantitative Clinical Pharmacology: Toward a Culture That Challenges the Status Quo.

Access lag to innovative therapies in Asian populations continues to present a challenge to global health. Recent progressive changes in the global regulatory landscape, including newer guidelines, are enabling simultaneous global drug development and near-simultaneous global drug registration. The International Conference on Harmonization (ICH) E17 guideline outlines general principles for the design and analysis of multiregional clinical trials (MRCTs). We posit that translational research and quantitative clinical pharmacology tools are core enablers for Asia-inclusive global drug development aligned with ICH E17 principles. Assessment of ethnic sensitivity should be initiated early in the development lifecycle to inform the need for, and extent of, Asian phase I ethno-bridging data. Relevant ethno-bridging data may be generated as standalone Asian phase I trials, as part of Western First-In-Human trials, or under accelerated development settings as a lead-in phase in an MRCT. Quantitative understanding of human clearance mechanisms and pharmacogenetic factors is vital to forecasting ethnic sensitivity in drug exposure using physiologically-based pharmacokinetic models. Stratification factors to control heterogeneity in MRCTs can be identified by reverse translational research incorporating pharmacometric disease models and model-based meta-analyses. Because epidemiological variations can extend to the molecular level, quantitative systems pharmacology models may be useful in forecasting how molecular variation in therapeutic targets or pathway proteins across populations might impact treatment outcomes. Through prospective evaluation of conservation in drug- and disease-related intrinsic and extrinsic factors, a pooled East Asian region can be implemented in Asia-inclusive MRCTs to maximize efficiency in substantiating evidence of benefit-risk for the region at-large with a Totality of Evidence approach.

A Comprehensive Review: Chronic Pain Sequelae in the Presence of Ehlers-Danlos Syndrome.

PURPOSE OF REVIEW: Patients diagnosed with Ehlers-Danlos syndromes (EDS), and especially those with the hypermobility subtype, often experience a diverse range of acute and chronic pain conditions throughout their lifetime. These can present in a variety of different phenotypes and comorbidities, making it difficult to develop structured treatment protocols. This review seeks to summarize the current literature to address old and novel treatments for EDS. RECENT FINDINGS: Historically, medications and surgery have been used to treat patients with EDS but with low efficacy. Newer therapies that have shown promising effects for both decreasing pain and increasing quality of life include physical/occupational therapy, transcutaneous electrical nerve stimulation units, trigger point injections, low-dose naltrexone, and laser therapy. In addition, addressing the psychosocial aspects of pain with EDS through methods like cognitive behavioral therapy and patient education has shown to be vital in minimizing pain. Most research also emphasizes that pain management should not only focus on pain reduction, but on helping reduce symptoms of hypermobility, central sensitization, and fatigue to make an impactful difference. Research on pain in EDS is still limited with good clinical practice guidelines often limited by poor sample size and lack of clinical studies. Treatment options should be structured based on the specific type of pain pathology and presenting symptoms of each patient and their comorbidities. Future research should attempt to prioritize larger sample sizes, clear definitions of EDS subtypes, randomized trials for treatment efficacy, and more studies dedicated to non-musculoskeletal forms of pain.

A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions.

PURPOSE: Polysorbates (PS) contain polyoxyethylene (POE) sorbitan/isosorbide fatty acid esters that can partially hydrolyze over time in liquid drug products to generate degradants and a remaining intact PS fraction with a modified ester distribution. The degradants are composed of free fatty acids (FFAs) --primarily lauric acid for PS20 and oleic acid for PS80-- and POE head groups. We previously demonstrated that under IV bag agitation conditions, mAb1 (a surface-active IgG4) aggregation increased with increasing amounts of degradants for PS20 but not for PS80. The purpose of this work is to understand the mechanism behind this observation. METHODS: The surface tension of the remaining intact PS fraction without degradants was modeled and compared with that of enzymatically degraded PS solutions. Next, mAb1 aggregation in saline was measured in the presence of laurate and oleate salts during static storage. Lastly, colloidal and conformational stability of mAb1 in the presence of these salts was investigated through differential scanning fluorimetry and dynamic light scattering under IV bag solution conditions. RESULTS: The surface tension was primarily influenced by FFAs rather than the modified ester distribution of the remaining intact PS. MAb1 bulk aggregation increased in the presence of laurate but not oleate salts. Both salt types increased the melting temperature of mAb1 indicating FFA-mAb1 interactions. However, only laurate salt increased mAb1 self-association potentially explaining the higher aggregation propensity in its presence. CONCLUSION: Our results help explain the observed differences between hydrolytically degraded PS20 and PS80 in affecting mAb1 aggregation under IV bag agitation conditions.

Tenapanor: A new treatment option for hyperphosphatemia in end stage kidney disease.

PURPOSE: This narrative review explores the currently published studies that have evaluated tenapanor for the treatment of hyperphosphatemia in end-stage kidney disease (ESKD) patients on hemodialysis. This medication's new phosphate lowering mechanism of action reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux by inhibition of the sodium/hydrogen exporter isoform 3 (NHE3). Tenapanor additionally prevents active transcellular phosphate absorption compensation by decreasing the expression of sodium phosphorus 2b transport protein (NaPi2b). METHODS: A comprehensive search of the literature was conducted using PubMed and ClinicalTrials.gov search engines. The search term "tenapanor hyperphosphatemia" was used for study retrieval. Results were limited to studies published in the English language and excluded review articles. Human, animal, and in vitro studies were included. No date range was specified. RESULTS: A total of 11 primary studies were identified and included in this review, the largest human study of which enrolled 236 patients. Each study is presented in table format along with measured end points. CONCLUSIONS: Tenapanor is the first drug in its class that lowers hyperphosphatemia in ESKD patients through a novel mechanism of action involving paracellular inactive transport. Although more studies are needed, early results indicate that tenapanor may have a place in managing hyperphosphatemia in ESKD patients both as monotherapy and as an adjunct to existing phosphate binder therapy.

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.

Toward safer opioid prescribing: effects of the TOWER intervention on HIV care providers.

ABSTRACTRates of opioid use disorder and associated deaths remain alarmingly high. Measures to address the epidemic have included reductions in opioid prescribing, in part guided by the Centers for Disease Control Opioid Prescribing Guideline (CDCG). While reductions in over-prescribing have occurred, these measures have also resulted in decreased access and adverse outcomes for some stable opioid-treated chronic pain patients. The TOWard SafER Opioid Prescribing (TOWER) intervention was designed to support HIV primary care providers in use of the CDCG and in decision-making and patient-provider communication regarding safe opioid prescribing. Eleven HIV primary care providers and 40 of their patients were randomized into intervention and control groups. Transcripts from 21 patient visits were analyzed, focusing on opioid and pain-related communications. Findings from this research indicate greater alignment with the CDCG among visits carried out with providers in the TOWER intervention group. However, control group visits were notably consistent with guideline recommendations in several key areas. Differences observed between the intervention and control group visits demonstrate intervention strengths, as well as areas where additional work needs to be done to ensure prescribing and communication consistent with the CDCG.

Impacts of lung cancer multidisciplinary meeting presentation: Drivers and outcomes from a population registry retrospective cohort study.

INTRODUCTION: Multidisciplinary Meetings (MDM) are recommended in routine lung cancer care, however its broader impacts demand further evaluation. We assessed the drivers and impacts of MDM presentation in the Victorian Lung Cancer Registry (VLCR). METHODS: We examined the effect of MDM presentation on receipt of treatment and survival in VLCR patients diagnosed between 2011 and 2020. We compared patient characteristics, drivers of MDM discussion and survival between the two groups. RESULTS: Of 9,628 patients, 5,900 (61.3%) were discussed at MDM, 3,728 (38.7%) were not. In the non-MDM group, a lower proportion received surgery (22.1% vs. 31.2%), radiotherapy (34.2% vs. 44.4%) and chemotherapy (44.7% vs. 49.0%). Patients were less likely to be discussed if ≥80 years (OR 0.73, p < 0.001), of ECOG performance status (PS) 4 (OR 0.23, p < 0.001), clinical stage IV (OR 0.34, p < 0.001) or referred from regional (OR 0.52, p < 0.001) or private hospital (OR 0.18, p < 0.001). MDM-presented patients had better median survival (1.70 vs 0.75 years, p < 0.001) and lower adjusted mortality risk (HR 0.75; 0.71-0.80, p < 0.001), a protective effect consistent across all hospital types. Undocumented PS, histopathology and clinical stage were associated with lower likelihood of MDM discussion and worse mortality. CONCLUSIONS: In the VLCR, being male, ≥80 years, of poorer PS, advanced clinical stage and poor clinical characterisation significantly disadvantaged patients in relation to MDM discussion. MDM-discussed patients were more likely to undergo treatment and had a 25% lower risk of mortality. This study supports the use of MDMs in lung cancer and identifies areas of inequity to be addressed.

Repeated adrenaline requirements for anaphylaxis.

We examined the pattern of adrenaline administration in patients presenting with anaphylaxis. Forty-four percent required repeated adrenaline administration, among whom there had been greater cardiorespiratory compromise. Repeated administration was more frequent in males and older patients, and those triggered by insect sting or unknown cause; no other patient factors were identified. This study supports the provision of two adrenaline auto-injectors to all anaphylaxis patients.

Relationship Between Multidrug-Resistant Enterobacterales and Obesity in Older Adults.

PURPOSE: The objective of our study was to determine if obesity is associated with the presence of multidrug-resistant (MDR) bacteria among Enterobacterales. PATIENTS AND METHODS: This two-center cohort study included adult hospitalized patients with at least one specimen sampled from any site for bacterial culture yielding an Enterobacterales bacterial species from November 2016 to May 2017. Study groups were stratified by obesity status based on body mass index <30 kg/m2 (non-obese) and ≥30 kg/m2 (obese). The primary outcome was the presence of gram-negative MDR bacteria defined as presumptive extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ceftriaxone resistance) or carbapenem-resistant Enterobacterales (CRE). A multivariable logistic regression model was fit to estimate the adjusted odds ratio while controlling for potential confounders. RESULTS: A total of 366 patients, 238 non-obese and 128 obese, were included. The most common gram-negative bacterial species identified was Escherichia coli (64.2%). There was a higher proportion of gram-negative MDR bacteria in obese versus non-obese patients (18.8 versus 11.3%, P=0.057). Obesity was independently associated with gram-negative MDR bacteria after controlling for confounders (adjusted odds ratio, 1.92; 95% CI 1.03-3.60). The association did not significantly vary by diabetes status (interaction term P=0.792). CONCLUSION: Among older adult hospitalized patients, obesity was independently associated with the presence of a gram-negative MDR bacteria (presumptive ESBL or CRE) in a culture.

Conjunctival Commensal Isolation and Identification in Mice.

The ocular surface was once considered immune privileged and abiotic, but recently it appears that there is a small, but persistent commensal presence. Identification and monitoring of bacterial species at the ocular mucosa have been challenging due to their low abundance and limited availability of appropriate methodology for commensal growth and identification. There are two standard approaches: culture based or DNA sequencing methods. The first method is problematic due to the limited recoverable bacteria and the second approach identifies both live and dead bacteria leading to an aberrant representation of the ocular space. We developed a robust and sensitive method for bacterial isolation by building upon standard microbiological culturing techniques. This is a swab-based technique, utilizing an "in-lab" made thin swab that targets the lower conjunctiva, followed by an amplification step for aerobic and facultative anaerobic genera. This protocol has allowed us to isolate and identify conjunctival species such as Corynebacterium spp., Coagulase Negative Staphylococcus spp., Streptococcus spp., etc. The approach is suitable to define commensal diversity in mice under different disease conditions.

Pseudomonas aeruginosa-induced nociceptor activation increases susceptibility to infection.

We report a rapid reduction in blink reflexes during in vivo ocular Pseudomonas aeruginosa infection, which is commonly attributed and indicative of functional neuronal damage. Sensory neurons derived in vitro from trigeminal ganglia (TG) were able to directly respond to P. aeruginosa but reacted significantly less to strains of P. aeruginosa that lacked virulence factors such as pili, flagella, or a type III secretion system. These observations led us to explore the impact of neurons on the host's susceptibility to P. aeruginosa keratitis. Mice were treated with Resiniferatoxin (RTX), a potent activator of Transient Receptor Potential Vanilloid 1 (TRPV1) channels, which significantly ablated corneal sensory neurons, exhibited delayed disease progression that was exemplified with decreased bacterial corneal burdens and altered neutrophil trafficking. Sensitization to disease was due to the increased frequencies of CGRP-induced ICAM-1+ neutrophils in the infected corneas and reduced neutrophil bactericidal activities. These data showed that sensory neurons regulate corneal neutrophil responses in a tissue-specific matter affecting disease progression during P. aeruginosa keratitis. Hence, therapeutic modalities that control nociception could beneficially impact anti-infective therapy.

Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex.

Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs.

Small Extracellular Vesicles Control Dendritic Spine Development through Regulation of HDAC2 Signaling.

The release of small extracellular vesicles (sEVs) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein-binding and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest, because HDAC2 regulates spine development, and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activation of HDAC2-dependent transcriptional programs.SIGNIFICANCE STATEMENT A role of small extracellular vesicles (sEVs; also called exosomes) in neuronal development is of particular interest, because sEVs could provide a major signaling modality between developing neurons when synapses are not fully functional or immature. However, knowledge of sEVs on neuron, and more precisely spine development, is limited. We provide several lines of evidence that sEVs released from developing cortical neurons regulate the development of dendritic spines via the regulation of HDAC2 signaling. This paracrine communication is temporally restricted during development because of the age-dependent decrease in sEV release as neurons mature and acquire spines.

Vedolizumab Concentrations in Breast Milk: Results from a Prospective, Postmarketing, Milk-Only Lactation Study in Nursing Mothers with Inflammatory Bowel Disease.

BACKGROUND AND OBJECTIVES: The safety of inflammatory bowel disease medications during lactation is of significant relevance to women of childbearing potential. Available data regarding the transfer of biologic agents for inflammatory bowel disease via breast milk are limited to case reports. The objective of this prospective postmarketing lactation study was to assess vedolizumab concentrations in breast milk from lactating vedolizumab-treated women with inflammatory bowel disease. METHODS: Breast milk was serially collected throughout the dosing interval from 11 patients receiving established intravenous vedolizumab 300-mg maintenance therapy every 8, 6, or 4 weeks. Maternal safety was also assessed. RESULTS: Vedolizumab was detectable in ~90% of milk samples collected from all patients. Following the day 1 dose, vedolizumab milk concentrations increased with a median of 3-4 days to peak concentration, and subsequently decreased exponentially. For the nine patients receiving vedolizumab every 8 weeks, the average relative infant dose was 20.9%. Using a mean trough serum concentration of 11.2 µg/mL from historical studies, the ratio of mean vedolizumab milk-to-serum concentration was ~ 0.4 to 2.2%, consistent with published data on vedolizumab and other monoclonal antibody therapeutics for inflammatory bowel disease. The maternal safety profile was similar to that observed in previous vedolizumab studies. Published vedolizumab studies also showed no adverse findings for infants breastfed by vedolizumab-treated mothers. CONCLUSIONS: Vedolizumab was present in human breast milk at a low level. The decision to use vedolizumab should balance the benefit of therapy to the mother and the potential risks to the infant. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02559713; registered 24 September, 2015.

A case study of evaluating bilateral lung dose for VMAT treatment planning using a partial sagittal arc.

Radiation pneumonitis (RP) is a potential toxic side effect of thoracic radiotherapy. Optimal planning techniques must maintain tumor coverage while limiting dose to normal lung tissue to reduce the risk of patients developing RP. The addition of a noncoplanar arc may be beneficial by increasing treatment angles and providing an ideal dose distribution for tumor coverage while decreasing dose to organs at risk (OAR). The purpose of this research was to compare the effects on the normal bilateral lung tissue receiving 20 Gy, 10 Gy and 5 Gy (V20, V10, V5) and the mean lung dose (MLD) values when medial lung tumors are treated with 3 partial coplanar arcs vs 2 partial coplanar arcs combined with a partial sagittal arc. Researchers hypothesized that a beam arrangement of 2 partial coplanar arcs and 1 partial sagittal arc would reduce V20, V10, V5, and MLD values when compared to a 3 partial coplanar arc plan. In a retrospective study of 5 patients with bulky, medial right lung lesions without nodal involvement, cases were planned with both a noncoplanar and a coplanar arc geometry. Results were evaluated using a two-tailed t-test to determine the statistical significance (p < 0.05) of changes to total lung volume analyzation metrics when a noncoplanar sagittal arc was incorporated compared to the standard lung treatment using only coplanar arcs. Although some patient cases showed minor improvement in the V20, V10, V5, and MLD metrics, the study results were not statistically significant and showed no advantage with the introduction of an anterior sagittal arc over a coplanar beam arrangement.

Assessment of Vedolizumab Disease-Drug-Drug Interaction Potential in Patients With Inflammatory Bowel Diseases.

Disease-drug-drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti-inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well-established positive benefit-risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4ß-hydroxycholesterol-to-cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.