Early Phase Research Articles

Evaluating tixagevimab/cilgavimab prophylaxis in allogeneic haematopoietic cell transplantation recipients for COVID-19 prevention.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients exhibit an increased risk of COVID-19, particularly in the early post-transplant phase, due to insufficient vaccine responses. This retrospective study investigated the incidence of SARS-CoV-2 infection in allo-HCT recipients who received tixagevimab/cilgavimab pre-exposure prophylaxis (T/C PrEP) compared to those who did not. Logistic regression, adjusted for sex, age, SARS-CoV-2 vaccination status and immunosuppressive treatment, revealed a significant reduction in the likelihood of SARS-CoV-2 infection risk with T/C PrEP (adjusted odds ratio aOR = 0.26 [0.07, 0.91]). These findings suggest the potential efficacy of monoclonal antibody PrEP in protecting this vulnerable patient population from COVID-19.

Stochastic model of vesicular stomatitis virus replication reveals mutational effects on virion production.

We present the first complete stochastic model of vesicular stomatitis virus (VSV) intracellular replication. Previous models developed to capture VSV's intracellular replication have either been ODE-based or have not represented the complete replicative cycle, limiting our ability to understand the impact of the stochastic nature of early cellular infections on virion production between cells and how these dynamics change in response to mutations. Our model accurately predicts changes in mean virion production in gene-shuffled VSV variants and can capture the distribution of the number of viruses produced. This model has allowed us to enhance our understanding of intercellular variability in virion production, which appears to be influenced by the duration of the early phase of infection, and variation between variants, arising from balancing the time the genome spends in the active state, the speed of incorporating new genomes into virions, and the production of viral components. Being a stochastic model, we can also assess other effects of mutations beyond just the mean number of virions produced, including the probability of aborted infections and the standard deviation of the number of virions produced. Our model provides a biologically interpretable framework for studying the stochastic nature of VSV replication, shedding light on the mechanisms underlying variation in virion production. In the future, this model could enable the design of more complex viral phenotypes when attenuating VSV, moving beyond solely considering the mean number of virions produced.

Impact of the COVID-19 pandemic on the prevalence of respiratory viral pathogens in patients with acute respiratory infection in Shanghai, China.

This study aimed to evaluate the impact of nonpharmaceutical interventions (NPIs) taken to combat COVID-19 on the prevalence of respiratory viruses (RVs) of acute respiratory infections (ARIs) in Shanghai. Samples from ARI patients were collected and screened for 17 respiratory viral pathogens using TagMan low density microfluidic chip technology in Shanghai from January 2019 to December 2020. Pathogen data were analyzed to assess changes in acute respiratory infections between 2019 and 2020. A total of 2,744 patients were enrolled, including 1,710 and 1,034 in 2019 and 2020, respectively. The total detection rate of RVs decreased by 149.74% in 2020. However, detection rates for human respiratory syncytial virus B (RSVB), human coronavirus 229E (HCoV229E), human coronavirus NL63 (HCoVNL63), and human parainfluenza virus 3 (HPIV3) increased by 91.89, 58.33, 44.68 and 24.29%, in 2020. The increased positive rates of RSVB, HPIV3, resulted in more outpatients in 2020 than in 2019. IFV detection rates declined dramatically across gender, age groups, and seasons in 2020. NPIs taken to eliminate COVID-19 had an impact on the prevalence of respiratory viral pathogens, especially the IFVs in the early phases of the pandemic. Partial respiratory viruses resurged with the lifting of NPIs, leading to an increase in ARIs infection.

Tracking the Impact of Koch-Carbonylated Organics During the Zeolite ZSM-5 Catalyzed Methanol-to-Hydrocarbons Process.

A methanol-based economy offers an efficient solution to current energy transition challenges, where the zeolite-catalyzed methanol-to-hydrocarbons (MTH) process would be a key enabler in yielding synthetic fuels/chemicals from renewable sources. Despite its original discovery over half a century ago over the zeolite ZSM-5, the practical application of this process in a CO2 -neutral scenario has faced several obstacles. One prominent challenge has been the intricate mechanistic complexities inherent in the MTH process over the zeolite ZSM-5, impeding its widespread adoption. This work takes a significant step forward by providing critical insights that bridge the gap in our understanding of the MTH process. It accomplishes this by connecting the (Koch-carbonylation-led) direct and dual cycle mechanisms, which operate during the early and steady-state phases of MTH catalysis, respectively. To unravel these mechanistic intricacies, we have performed catalytic and operando (i.e., UV/Vis coupled with an online mass spectrometer) and solid-state NMR spectroscopic-based investigations on the MTH process, involving co-feeding methanol and acetone (cf. a key Koch-carbonylated species), including selective isotope-labeling studies. Our iterative research approach revealed that (Koch-)carbonyl group selectively promotes the side-chain mechanism within the arene cycle of the dual cycle mechanism, impacting the preferential formation of BTX fraction (i.e., benzene-toluene-xylene) primarily.

BIM-based multi-objective optimization framework for volumetric analysis of building projects

Purpose The purpose of this paper is to develop a building information modelling (BIM)-based multi-objective optimization (MOO) framework for volumetric analysis of buildings during early design stages. The objective is to optimize volumetric spaces (3D) instead of 2D spaces to enhance space utilization, thermal comfort, constructability and rental value of buildings Design/methodology/approach The integration of two fundamental concepts – BIM and MOO, forms the basis of proposed framework. In the early design phases of a project, BIM is used to generate precise building volume data. The non-sorting genetic algorithm-II, a MOO algorithm, is then used to optimize extracted volume data from 3D BIM models, considering four objectives: space utilization, thermal comfort, rental value and construction cost. The framework is implemented in context of a school of architecture building project. Findings The findings of case study demonstrate significant improvements resulting from MOO of building volumes. Space utilization increased by 30%, while thermal comfort improved by 20%, and construction costs were reduced by 10%. Furthermore, rental value of the case study building increased by 33%. Practical implications The proposed framework offers practical implications by enabling project teams to generate optimal building floor layouts during early design stages, thereby avoiding late costly changes during construction phase of project. Originality/value The integration of BIM and MOO in this study provides a unique approach to optimize building volumes considering multiple factors during early design stages of a project

Internet Use and Effects on Mental Well-being During the Lockdown Phase of the COVID-19 Pandemic in Younger Versus Older Adults: Observational Cross-Sectional Study.

Majority of individuals, including both younger and older adults, had to adapt to digital means to cope with lockdown measures and pandemic-induced lifestyle changes during the COVID-19 pandemic. While internet accessibility was beneficial during the pandemic, existing literature suggests that excessive use could lead to the rise of problematic internet use in adolescents and younger adults. However, the effects on older adults remain unclear. This study aimed to examine differences in internet use during the lockdown phase of the COVID-19 pandemic and explore how age differences in mental health could be explained by time spent on the internet. A door-to-door survey of a nationally representative sample of 602 adults in Singapore was carried out using computer-assisted personal interviewing during the early phase of the COVID-19 pandemic (October to November 2020). Participants were categorized into younger (21-59 years old) and older (60 years or above) age groups. We assessed self-reported measures of depression, anxiety, and stress; psychosocial adaptability; ability to perform essential activities; social support; health status; digital media use patterns, and time spent on the internet. Procedures complied with existing safe distancing measures. Older adults reported being less able to use digital platforms to meet needs and acquire information updates compared with younger adults during the lockdown period of the pandemic. Older adults spent significantly less time on the internet for both work and personal uses per day (mean 146.00 min, SD 9.18 min) compared with younger adults (mean 433.27 min, SD 14.32 min). Significant age differences in depression, anxiety, and stress were found, with younger adults showing poorer mental health. Mediation analysis showed that age differences in depression, anxiety, and stress were partially explained by time spent on the internet. These variables together explained 43%, 40%, and 40% of the variances in depression, anxiety, and stress scores, respectively. The findings showed that younger adults spent significantly more time on the internet compared with older adults during the lockdown phase of the pandemic. They were also ahead in their ability to use digital resources to meet needs and engage socially compared with older adults. Despite this, the mental health of younger adults was poor, and this was partially accounted for by the amount of time spent on the internet. Since past research suggests that excessive time spent on the internet could lead to disordered use, the benefits brought by digital technologies could have been attenuated during the lockdown phase of the pandemic. Considering this potential negative effect, it is imperative to educate both young and old adults in the appropriate use of information and communication technology.

Number of intra-operative cyclic knee motion required to achieve stable graft tension in anterior cruciate ligament reconstruction; a prospective clinical study.

Applying pretension by cyclic knee motion immediately before graft fixation in anterior cruciate ligament (ACL) reconstruction surgery decreases graft elongation during the postoperative course. However, the expected change in graft tension caused by cyclic knee motion remains unclear. We measured graft tension changes caused by cyclic knee motion during double-bundle ACL reconstruction. We included 39 patients undergoing primary anatomical double-bundle ACL reconstruction with autologous hamstrings as graft sources, at multiple centers between February 2021 and August 2022. After securing the anteromedial (AM) and posterolateral (PL) bundle grafts to the femoral cortex, they were initially tensioned to 40 N per bundle. After 10 cycles of knee extension and flexion motion, ranging from 0 to 90-110°, tension was re-measured and re-tensioned to 40 N if the graft tension had decreased. This was repeated thrice for 10 cycles on each graft. Every 10 cycles, we recorded graft tension changes (ΔGT) and compared the mean ΔGT in the AM and PL bundles. Furthermore, we assessed relationships between total ΔGT in each bundle, age, sex, and graft diameter. Twenty-five women and 14 men with a mean age of 27.4 ± 12.4 years were included. The mean ΔGT in AM and PL bundles after every 10 cycles were 6.6 ± 3.7 N, 3.0 ± 2.3 N, 1.4 ± 1.5 N, and 9.9 ± 3.8 N, 4.9 ± 2.6 N, and 2.5 ± 1.9 N, respectively. There were significant differences in ΔGT in both bundles after every 10 cycles (p < 0.01). ΔGT in the AM bundle was significantly lower than in the PM bundle at the same number of cycles (p < 0.01). No correlation was observed between ΔGT in either bundle and age, sex, or graft diameter. The initially applied graft tension decreased by intra-operative cyclic knee movement, and the changes in graft tension decreased after retention and repeated cycles. Three sets of 10 cycles knee motion may avoid initial tension loss of the hamstring autograft in the early phase after double-bundle ACL reconstruction.

Relationship between Serum Glial Fibrillary Acidic Protein and Neurogranin Levels and Cognition in Multiple Sclerosis

Multiple sclerosis is an inflammatory neurodegenerative disorder, and cognitive problems occur in the early and late phases of the disease. The purpose of this study was to investigate the relationship between serum glial fibrillary acidic protein and neurogranin levels and cognition in patients with multiple sclerosis (MS). Twenty-three patients and 25 healthy controls were included in the study. Serum glial fibrillary acidic protein (GFAP) and neurogranin (NRGN) levels were determined on blood samples from patients and controls. Disease duration and EDSS scores of patients were recorded, and the Montreal Cognitive Assessment (MOCA) scale was used for cognitive assessment. There was no statistically significant difference between the two groups in terms of serum NRGN and GFAP levels. MOCA scores were lower in the patient group than in the healthy control group. No statistically significant correlation was found between NRGN and GFAP serum levels and MOCA scores. Our study showed that there was no statistically significant association between serum NRGN and GFAP levels and cognition in MS patients. This study is the first to examine serum GFAP and NRGN levels in the context of cognition in MS.

The Economics of Audit Production: What Matters for Audit Quality? An Empirical Analysis of the Role of Midlevel Managers within the Audit Firm

ABSTRACT As audits of public companies are labor intensive, require a variety of team members, and involve year-round work, practitioners and academics have increasingly focused on identifying audit production factors that drive audit quality. Using proprietary data, we analyze the cost-benefit tradeoffs of two audit production characteristics, client expertise and the relative amount of auditing done during the early phases of the audit, and find that both are associated with more effective audits and higher fees. We analyze whether the influence of these characteristics varies across audit team members. We find that middle manager production characteristics explain audit effectiveness and higher fees and relatively more so than those of lead/review partners. These results extend the literature and practitioner discussions about drivers of audit quality by highlighting the importance of middle management, which, to our knowledge, has largely been overlooked by the archival audit literature and regulatory guidance on audit quality indicators. Data Availability: This paper exploits proprietary PCAOB data. Data descriptions are available in the text. JEL Classifications: D20; D22; J24; L23; M11; M4; M42; M48.

Computational evidences of a misfolding event in an aggregation-prone light chain preceding the formation of the non-native pathogenic dimer.

Antibody light chain amyloidosis is a disorder in which protein aggregates, mainly composed of immunoglobulin light chains, deposit in diverse tissues impairing the correct functioning of organs. Interestingly, due to the high susceptibility of antibodies to mutations, AL amyloidosis appears to be strongly patient-specific. Indeed, every patient will display their own mutations that will make the proteins involved prone to aggregation thus hindering the study of this disease on a wide scale. In this framework, determining the molecular mechanisms that drive the aggregation could pave the way to the development of patient-specific therapeutics. Here, we focus on a particular patient-derived light chain, which has been experimentally characterized. We investigated the early phases of the aggregation pathway through extensive full-atom molecular dynamics simulations, highlighting a structural rearrangement and the exposure of two hydrophobic regions in the aggregation-prone species. Next, we moved to consider the pathological dimerization process through docking and molecular dynamics simulations, proposing a dimeric structure as a candidate pathological first assembly. Overall, our results shed light on the first phases of the aggregation pathway for a light chain at an atomic level detail, offering new structural insights into the corresponding aggregation process.

Structure Discovery in Atomic Force Microscopy Imaging of Ice.

The interaction of water with surfaces is crucially important in a wide range of natural and technological settings. In particular, at low temperatures, unveiling the atomistic structure of adsorbed water clusters would provide valuable data for understanding the ice nucleation process. Using high-resolution atomic force microscopy (AFM) and scanning tunneling microscopy, several studies have demonstrated the presence of water pentamers, hexamers, and heptamers (and of their combinations) on a variety of metallic surfaces, as well as the initial stages of 2D ice growth on an insulating surface. However, in all of these cases, the observed structures were completely flat, providing a relatively straightforward path to interpretation. Here, we present high-resolution AFM measurements of several water clusters on Au(111) and Cu(111), whose understanding presents significant challenges due to both their highly 3D configuration and their large size. For each of them, we use a combination of machine learning, atomistic modeling with neural network potentials, and statistical sampling to propose an underlying atomic structure, finally comparing its AFM simulated images to the experimental ones. These results provide insights into the early phases of ice formation, which is a ubiquitous phenomenon ranging from biology to astrophysics.

Fibrosis Progression in Patients with Budd–Chiari Syndrome and Transjugular Intrahepatic Portosystemic Shunt (TIPS): A Long-Term Study Using Transient Elastography

Hepatic vein outflow obstruction causes congestion of the liver, leading to necrosis, fibrosis, and portal hypertension (PH). A transjugular intrahepatic portosystemic shunt (TIPS) reduces congestion and PH by providing artificial outflow. The aim of the study was to investigate fibrosis progression in patients with Budd–Chiari syndrome (BCS) and TIPS using transient elastography (TE). From 2010 to 2022, 25 patients received 80 TEs using FibroScan®, Echosens, Paris, France (3.2 ± 2.1 per patient). TIPS function was assessed via Doppler ultrasound or radiological intervention. At the time of TE examination, 21 patients had patent shunts. Four patients had occluded shunts but normal pressure gradients during the intervention. The first TE measurement performed 9.8 ± 6.8 years after the BCS diagnosis showed stiffness values of 24.6 ± 11.5 kPa. A second or last measurement performed 7.0 ± 2.9 years after the first measurement showed similar stiffness values of 24.1 ± 15.7 kPa (p = 0.943). Except for three patients, the liver stiffness was always &gt;12 kPa, indicating advanced fibrosis. Stiffness values obtained &lt;5 years (n = 8, 23.8 ± 9.2 kPa) or &gt;5 years after the BCS diagnosis (24.9 ± 12.7 kPa) did not differ (p = 0.907). In addition, stiffness was not related to the interval between BCS and TIPS implantation (p = 0.999). One patient received liver transplantation, and two patients died from non-hepatic causes. Most patients developed mild to moderate cirrhosis, possibly during the early phase of the disease. Timing of TIPS did not influence fibrosis progression. This and the release of portal hypertension may argue in favor of a generous TIPS implantation practice in patients with BCS.

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach.

Introduction. Infection caused by Mycobacterium tuberculosis (M. tb) is still a leading cause of mortality worldwide with estimated 1.4 million deaths annually.Hypothesis/Gap statement. Despite macrophages' ability to kill bacterium, M. tb can grow inside these innate immune cells and the exploration of the infection has traditionally been characterized by a one-sided relationship, concentrating solely on the host or examining the pathogen in isolation.Aim. Because of only a handful of M. tb-host interactions have been experimentally characterized, our main goal is to predict protein-protein interactions during the early phases of the infection.Methodology. In this work, we performed an integrative computational approach that exploits differentially expressed genes obtained from Dual RNA-seq analysis combined with known domain-domain interactions.Results. A total of 2381 and 7214 genes were identified as differentially expressed in M. tb and in THP-1-like macrophages, respectively, revealing different transcriptional profiles in response to infection. Over 48 h of infection, the host-pathogen network revealed 25 016 PPIs. Analysis of the resulting predicted network based on cellular localization information of M. tb proteins, indicated the implication of interacting nodes including the bacterial PE/PPE/PE_PGRS family. In addition, M. tb proteins interacted with host proteins involved in NF-kB signalling pathway as well as interfering with the host apoptosis ability via the potential interaction of M. tb TB16.3 with human TAB1 and M. tb GroEL2 with host protein kinase C delta, respectively.Conclusion. The prediction of the full range of interactions between M. tb and host will contribute to better understanding of the pathogenesis of this bacterium and may provide advanced approaches to explore new therapeutic targets against tuberculosis.

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson’s Disease

Assessing imaging biomarker in the prodromal and early phases of Parkinson’s disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD.

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis.

Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.

The effect of the conduit size on middle-term outcomes in patients with extracardiac total cavopulmonary connection.

The 18- and 16-mm conduits in extracardiac total cavopulmonary connection (eTCPC) were reported to be optimal based on energy loss and flow stagnation at the relatively early phase. However, because the artificial conduit lacks growth potential, we have recently encountered some cases in which the conduit needs to be changed several years after eTCPC. These cases prompted us to reconsider the surgical strategy for eTCPC. We reviewed our 20-year single-centre experience with eTCPC patients (n = 256) to compare the 18-mm conduit (n = 195) and 16-mm conduit (n = 61) in terms of mortality and morbidity. The 16-mm conduit was used significantly more frequently in patients whose main chamber was right ventricle (P < 0.001). There was also a significant difference in preoperative inferior vena cava pressure (P = 0.008). There was a significant difference in the actuarial rate of freedom from late-occurring complications, including mortality, between the 2 groups (P = 0.003). There was a significant difference in the actuarial rate of reoperation-free survival (P = 0.042); however, there was no significant difference in resurgical intervention for the conduit (P = 0.333). In multivariate analysis, preoperative inferior vena cava pressure was an independent predictor for late-occurring complications (hazard ratio 1.19; P = 0.026). Conduit size (18 or 16 mm) itself was not an independent predictive factor for late-occurring complications (P = 0.690). The mid-term clinical outcomes in patients who underwent eTCPC were excellent with low mortality. Preoperative inferior vena cava pressure was the only predictive risk factor for postoperative morbidity, and the 16 mm conduit was not predictive thereof.

Predicting Long-Term Endothelial Cell Loss after Preloaded Descemet Membrane Endothelial Keratoplasty in Fuchs’ Endothelial Corneal Dystrophy: A Mathematical Model

(1) Background: This study offers a biexponential model to estimate corneal endothelial cell decay (ECD) following preloaded “endothelium-in” Descemet membrane endothelial keratoplasty (DMEK) in Fuchs’ endothelial corneal dystrophy (FECD) patients; (2) Methods: A total of 65 eyes undergoing DMEK alone or combined with cataract surgery were evaluated. The follow-up period was divided into an early phase (first 6 months) and a late phase (up to 36 months). Endothelial cell count (ECC) and endothelial cell loss (ECL) were analyzed; (3) Results: The half time of the ECD was 3.03 months for the early phase and 131.50 months for the late phase. The predicted time-lapse interval to reach 500 cells/mm2 was 218 months (18.17 years), while the time-lapse interval to reach 250 cells/mm2 was 349 months (29.08 years). There was no statistically significant difference between the ECL in DMEK combined with cataract extraction and DMEK alone at 24 months (p ≥ 0.20). At the late phase, long-term ECL prediction revealed a lower ECC half time in patients undergoing DMEK combined with cataract surgery (98.05 months) than DMEK alone (250.32 months); (4) Conclusions: Based on the mathematical modeling, a predicted average half-life of a DMEK graft could reach 18 years in FECD. Moreover, combining cataract extraction with DMEK could result in excessive ECL in the long term.

The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of the glymphatic system, which is mainly active during sleep. Changes in sleep and circadian rhythms are present not only in overt neurodegenerative diseases but also in their early, prodromal, and preclinical phases, supporting that they precede (and contribute to) the development of neurodegeneration. This narrative review provides a brief overview of sleep and circadian rhythm disruption in neurodegeneration, highlights the bidirectional relationship between sleep changes and neurodegeneration, and addresses future perspectives, in particular, whether sleep changes are able to predict neurodegeneration and the potential sleep actionability to prevent or modulate the development of neurodegenerative diseases.

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.

Ventilation Management in a Patient with Ventilation–Perfusion Mismatch in the Early Phase of Lung Injury and during the Recovery

Chest trauma is one of the most serious and difficult injuries, with various complications that can lead to ventilation–perfusion (V/Q) mismatch and systemic hypoxia. We are presenting a case of a 53-year-old male with no chronic therapy who was admitted to the Intensive Care Unit due to severe respiratory failure after chest trauma. He developed a right-sided pneumothorax, and then a thoracic drain was placed. On admission, the patient was hemodynamically unstable and tachypneic. He was intubated and mechanically ventilated, febrile (38.9 °C) and unconscious. A lung CT showed massive non-ventilated areas, predominantly in the right lung, guiding repeated therapeutic and diagnostic bronchoalveolar lavages. He was ventilated with PEEP of 10 cmH2O with a FiO2 of 0.6–0.8. Empirical broad-spectrum antimicrobial therapy was immediately initiated. Both high FiO2 and moderate PEEP were maintained and adjusted according to the current blood gas values and oxygen saturation. He was weaned from mechanical ventilation, and non-invasive oxygenation was continued. After Stenotrophomonas maltophilia was identified and treated with sulfamethoxazole/trimethoprim, a regression of lung infiltrates was observed. In conclusion, both ventilatory and antibiotic therapy were needed to improve the oxygenation and outcome of the patient with S. maltophilia pneumonia and V/Q mismatch.