Accelerating development of engineered T cell therapies in the EU: current regulatory framework for studying multiple product versions and T2EVOLVE recommendations.

To accelerate the development of Advanced Therapy Medicinal Products (ATMPs) for patients suffering from life-threatening cancer with limited therapeutic options, regulatory approaches need to be constantly reviewed, evaluated and adjusted, as necessary. This includes utilizing science and risk-based approaches to mitigate and balance potential risks associated with early clinical research and a more flexible manufacturing paradigm. In this paper, T2EVOLVE an Innovative Medicine Initiative (IMI) consortium explores opportunities to expedite the development of CAR and TCR engineered T cell therapies in the EU by leveraging tools within the existing EU regulatory framework to facilitate an iterative and adaptive learning approach across different product versions with similar design elements or based on the same platform technology. As understanding of the linkage between product quality attributes, manufacturing processes, clinical efficacy and safety evolves through development and post licensure, opportunities are emerging to streamline regulatory submissions, optimize clinical studies and extrapolate data across product versions reducing the need to perform duplicative studies. It is worth noting that this paper is focusing on CAR- and TCR-engineered T cell therapies but the concepts may be applied more broadly to engineered cell therapy products (e.g., CAR NK cell therapy products).

The Influence of Thermal and Mechanical Stress on the Electrical Conductivity of ITO-Coated Polycarbonate Films.

The influence of thermomechanical stress on the conductivity of indium tin oxide (ITO)-coated polycarbonate (PC) films was investigated. PC is the industry's standard material for window panes. ITO coatings on polyethylene terephthalate (PET) films are the main commercially available option; as such, most investigations refer to this combination. The investigations in this study aim to investigate the critical crack initiation strain at different temperatures and crack initiation temperatures for two different coating thicknesses and for a commercially available PET/ITO film for validation purposes. Additionally, the cyclic load was investigated. The results show the comparatively sensitive behavior of the PC/ITO films, with a crack initiation strain at room temperature of 0.3-0.4% and critical temperatures of 58 °C and 83 °C, with high variation depending on the film's thickness. Under thermomechanical loading, the crack initiation strain decreases with increasing temperatures.

Stabilization of phenanthrene anions in helium nanodroplets.

It has been debated for years if the polycyclic aromatic hydrocarbon phenanthrene exists in its anionic form, or, in other words, if its electron affinity (EA) is positive or negative. In this contribution we confirm that the bare phenanthrene anion Ph- created in a binary collision with an electron at room temperature has a lifetime shorter than microseconds. However, the embedding of neutral phenanthrene molecules in negatively charged helium nanodroplets enables the formation of phenanthrene anions by charge transfer processes and the stabilization of the latter in the ultracold environment. Gentle shrinking of the helium matrix of phenanthrene-doped HNDs by collisions with helium gas makes the bare Ph- visible by high-resolution mass spectrometry. From these and previous measurements we conclude, that the EA of phenanthrene is positive and smaller than 24.55 meV.

Helium structures around SF5+ and SF6+: novel intermolecular potential and mass spectrometry experiments.

Helium clusters around the recently experimentally observed sulphur hexafluoride SF6+ and sulphur pentafluoride SF5+ ions are investigated using a combined experimental and theoretical effort. Mass spectrometry ion yields are obtained and the energetics and structure of the corresponding HeN-SF6+ and HeN-SF5+ clusters are analyzed using path integral molecular dynamics calculations as a function of N, the number of He atoms, employing a new intermolecular potential describing the interaction between the dopant and the surrounding helium. The new force field is optimized on benchmark potential energy ab initio calculations and represented by improved Lennard-Jonnes analytical expressions. This procedure improves the previous potentials employed in similar simulations for neutral SF6 attached to helium nanodroplets. The theoretical analysis explains the characteristic features observed in the experimental ion yields which suggest the existence of stable configurations at specific sizes.

Adsorption of Helium on Small Cationic PAHs: Influence of Hydrocarbon Structure on the Microsolvation Pattern.

The adsorption of up to ∼100 helium atoms on cations of the planar polycyclic aromatic hydrocarbons (PAHs) anthracene, phenanthrene, fluoranthene, and pyrene was studied by combining helium nanodroplet mass spectrometry with classical and quantum computational methods. Recorded time-of-flight mass spectra reveal a unique set of structural features in the ion abundance as a function of the number of attached helium atoms for each of the investigated PAHs. Path-integral molecular dynamics simulations were used with a polarizable potential to determine the underlying adsorption patterns of helium around the studied PAH cations and in good general agreement with the experimental data. The calculated structures of the helium-PAH complexes indicate that the arrangement of adsorbed helium atoms is highly sensitive toward the structure of the solvated PAH cation. Closures of the first solvation shell around the studied PAH cations are suggested to lie between 29 and 37 adsorbed helium atoms depending on the specific PAH cation. Helium atoms are found to preferentially adsorb on these PAHs following the 3×3 commensurate pattern common for graphitic surfaces, in contrast to larger carbonaceous molecules like corannulene, coronene, and fullerenes that exhibit a 1 × 1 commensurate phase.

Splashing of Large Helium Nanodroplets upon Surface Collisions.

In the present work we observe that helium nanodroplets colliding with surfaces can exhibit splashing in a way that is analogous to classical liquids. We use transmission electron microscopy and mass spectrometry to demonstrate that neutral and ionic dopants embedded in the droplets are efficiently backscattered in such events. High abundances of weakly bound He-tagged ions of both polarities indicate a gentle extraction mechanism of these ions from the droplets upon collision with a solid surface. This backscattering process is observed for dopant particles with masses up to 400 kilodaltons, indicating an unexpected mechanism that effectively lowers deposition rates of nanoparticles formed in helium droplets.

Long-Lived Nuclear Coherences inside Helium Nanodroplets.

Much of our knowledge about dynamics and functionality of molecular systems has been achieved with femtosecond time-resolved spectroscopy. Despite extensive technical developments over the past decades, some classes of systems have eluded dynamical studies so far. Here, we demonstrate that superfluid helium nanodroplets, acting as a thermal bath of 0.4 K temperature to stabilize weakly bound or reactive systems, are well suited for time-resolved studies of single molecules solvated in the droplet interior. By observing vibrational wave packet motion of indium dimers (In_{2}) for tens of picoseconds, we demonstrate that the perturbation imposed by this quantum liquid can be lower by a factor of 10-100 compared to any other solvent, which uniquely allows us to study processes depending on long nuclear coherence in a dissipative environment. Furthermore, tailor-made microsolvation environments inside droplets will enable us to investigate the solvent influence on intramolecular dynamics in a wide tuning range from molecular isolation to strong molecule-solvent coupling.

Fall Risk in Relation to Individual Physical Activity Exposure in Patients with Different Neurodegenerative Diseases: a Pilot Study.

Falls in patients with neurodegenerative diseases (NDDs) have enormous detrimental consequences. A better understanding of the interplay between physical activity (PA) and fall risk might help to reduce fall frequency. We aimed to investigate the association between sensor-based PA and fall risk in NDDs, using "falls per individual PA exposure time" as a novel measure. Eighty-eight subjects (n = 31 degenerative ataxia (DA), n = 14 Parkinson's disease (PD), n = 12 progressive supranuclear palsy (PSP) and 31 healthy controls) were included in this pilot study. PA was recorded in free-living environments with three-axial accelerometers (activPAL™) over 7 days. Falls were prospectively assessed over 12 months. Fall incidence was calculated by (i) absolute number of falls per person years (py) and (ii) falls per exposure to individual PA. Absolute fall incidence was high in all three NDDs, with differing levels (DA, 9 falls/py; PD, 14 falls/py; PSP, 29 falls/py). Providing a more fine-grained view on fall risk, correction for individual exposure to PA revealed that measures of low walking PA were associated with higher fall incidence in all three NDDs. Additionally, higher fall incidence was associated with more sit-to-stand transfers in PD and longer walking bouts in PSP. Our results suggest that low walking PA is a risk factor for falls in DA, PD and PSP, indicating the potential benefit of increasing individual PA in these NDDs to reduce fall risk. Moreover, they show that correction for individual exposure to PA yields a more differentiated view on fall risk within and across NDDs.

Influences of Age and Emotion on Source Guessing: Are Older Adults More Likely to Show Fear-Relevant Illusory Correlations?

OBJECTIVES: The present study investigates age differences in the vulnerability to illusory correlations between fear-relevant stimuli and threatening information. METHOD: Younger and older adults saw pictures of threatening snakes and nonthreatening fish, paired with threatening and nonthreatening context information ("poisonous" and "nonpoisonous") with a null contingency between animal type and poisonousness. In a source monitoring test, participants were required to remember whether an animal was associated with poisonousness or nonpoisonousness. Illusory correlations were implicitly measured via a multinomial model. One advantage of this approach is that memory and guessing processes can be assessed independently. An illusory correlation would be reflected in a higher probability of guessing that a snake rather than a fish was poisonous if the poisonousness of the animal was not remembered. RESULTS: Older adults showed evidence of illusory correlations in source guessing while younger adults did not; instead they showed evidence of probability matching. Moreover, snake fear was associated with increased vulnerability to illusory correlations in older adults. DISCUSSION: The findings confirm that older adults are more susceptible to fear-relevant illusory correlations than younger adults.

Association between vestibulo-ocular reflex suppression, balance, gait, and fall risk in ageing and neurodegenerative disease: protocol of a one-year prospective follow-up study.

BACKGROUND: Falls frequency increases with age and particularly in neurogeriatric cohorts. The interplay between eye movements and locomotion may contribute substantially to the occurrence of falls, but is hardly investigated. This paper provides an overview of current approaches to simultaneously measure eye and body movements, particularly for analyzing the association of vestibulo-ocular reflex (VOR) suppression, postural deficits and falls in neurogeriatric risk cohorts. Moreover, VOR suppression is measured during head-fixed target presentation and during gaze shifting while postural control is challenged. Using these approaches, we aim at identifying quantitative parameters of eye-head-coordination during postural balance and gait, as indicators of fall risk. METHODS/DESIGN: Patients with Progressive Supranuclear Palsy (PSP) or Parkinson's disease (PD), age- and sex-matched healthy older adults, and a cohort of young healthy adults will be recruited. Baseline assessment will include a detailed clinical assessment, covering medical history, neurological examination, disease specific clinical rating scales, falls-related self-efficacy, activities of daily living, neuro-psychological screening, assessment of mobility function and a questionnaire for retrospective falls. Moreover, participants will simultaneously perform eye and head movements (fixating a head-fixed target vs. shifting gaze to light emitting diodes in order to quantify vestibulo-ocular reflex suppression ability) under different conditions (sitting, standing, or walking). An eye/head tracker synchronized with a 3-D motion analysis system will be used to quantify parameters related to eye-head-coordination, postural balance, and gait. Established outcome parameters related to VOR suppression ability (e.g., gain, saccadic reaction time, frequency of saccades) and motor related fall risk (e.g., step-time variability, postural sway) will be calculated. Falls will be assessed prospectively over 12 months via protocols and monthly telephone interviews. DISCUSSION: This study protocol describes an experimental setup allowing the analysis of simultaneously assessed eye, head and body movements. Results will improve our understanding of the influence of the interplay between eye, head and body movements on falls in geriatric high-risk cohorts.

Remembering the snake in the grass: Threat enhances recognition but not source memory.

Research on the influence of emotion on source memory has yielded inconsistent findings. The object-based framework (Mather, 2007) predicts that negatively arousing stimuli attract attention, resulting in enhanced within-object binding, and, thereby, enhanced source memory for intrinsic context features of emotional stimuli. To test this prediction, we presented pictures of threatening and harmless animals, the color of which had been experimentally manipulated. In a memory test, old-new recognition for the animals and source memory for their color was assessed. In all 3 experiments, old-new recognition was better for the more threatening material, which supports previous reports of an emotional memory enhancement. This recognition advantage was due to the emotional properties of the stimulus material, and not specific for snake stimuli. However, inconsistent with the prediction of the object-based framework, intrinsic source memory was not affected by emotion.

National survey of paediatric audiological services for diagnosis and intervention in the South African private health care sector.

OBJECTIVE: A national survey of early hearing detection and intervention services was undertaken to describe the current status of diagnostic and intervention services in the South African private health care sector. METHODS: All private hospitals with obstetric units (n = 166) were surveyed telephonically. The data was integrated with data collected from self-administered questionnaires subsequently distributed nationally to private audiology practices providing hearing screening at the respective hospitals reporting hearing screening services (n = 87). Data was analysed descriptively to yield national percentages and frequency distributions. RESULTS: Average reported age at diagnosis was 11 months. Most participants (74%) indicated that less than 20% of infants fitted with hearing aids received amplification before the age of 6 months. Most (64%) participants indicated that the average period between confirmed diagnosis and hearing aid fitting was 1 month, on par with international benchmarks. Only 16%-23% of participants included all diagnostic procedures recommended by the Health Professions Council of South Africa's 2007 position statement for minimum diagnostic test batteries for infants and young children. CONCLUSIONS: Diagnosis of hearing loss, hearing aid fitting and audiological intervention is delayed significantly in the South African private health care sector. Improved services should include integrated systematic hospital-based screening as part of birthing packages with diagnostic referral to specialist paediatric audiologists for accurate assessment and management of patients in a timely manner.

Early detection of infant hearing loss in the private health care sector of South Africa.

OBJECTIVE: A national survey of early hearing detection services was undertaken to describe the demographics, protocols and performance of early hearing detection, referral, follow-up and data management practices in the private health care sector of South Africa. METHODS: All private hospitals with obstetric units (n=166) in South Africa were surveyed telephonically. This data was incorporated with data collected from self-administered questionnaires subsequently distributed nationally to audiology private practices providing hearing screening at the respective hospitals reporting hearing screening services (n=87). Data was analyzed descriptively to yield national percentages and frequency distributions and possible statistical associations between variables were explored. RESULTS: Newborn hearing screening was available in 53% of private health care obstetric units in South Africa of which only 14% provided universal screening. Most (81%) of the healthy baby screening programs used only otoacoustic emission screening. Auditory brainstem response screening was employed by 24% of neonatal intensive care unit screening programs with only 16% repeating auditory brainstem response screening during the follow-up screen. Consequently 84% of neonatal intensive care unit hearing screening programs will not identify auditory neuropathy. A referral rate of less than 5% for diagnostic assessments was reported by 80% of universal programs. Follow-up return rates were reported to exceed 70% by only 28% of programs. Using multiple methods of reminding parents did not significantly increase reported follow-up return rates. Data management was mainly paper based with only 10% of programs using an electronic database primarily to manage screening data. CONCLUSIONS: A shortage of programs and suboptimal and variable protocols for early hearing detection, follow-up and data management in existing programs mean the majority of babies with hearing loss in the South African private health care sector will not be identified early. Newborn hearing screening must be integrated with hospital-based birthing services, ideally with centralized data management and quality control.

Newborn hearing screening in the private health care sector - a national survey.

OBJECTIVES: To determine: (i) the national status of newborn hearing screening services in the private health care sector of South Africa; (ii) screening approaches implemented; and (iii) challenges to screening implementation. DESIGN: A descriptive national survey in the private sector of South Africa was conducted within a quantitative paradigm. METHOD: All private health sector institutions with obstetric units (N=166) were surveyed telephonically and self-administered questionnaires were subsequently sent to all audiologists in private practice (N=87) who provide newborn hearing screening services at the units with hearing screening. RESULTS: Nationally 53% of private sector obstetric units offer some form of newborn hearing screening. Universal hearing screening was only offered by 14% of units, while the most common approaches were universal screening on some days of the week (18%) and screening on request (18%). The most prominent challenge to successful screening implementation was the apparent omission of newborn hearing screening from maternity birthing packages at the health care institutions. CONCLUSION: The vast majority of newborns nationally are not screened for hearing loss, and existing programmes are not sufficiently systematic and integrated to ensure adequate coverage. Hospital management and paediatric health services must prioritise hearing screening as part of standard of care birthing services.

O ácido 2-tiotiazolidina-4 carboxílico (TTCA) como biomarcador da exposiçäo ao sulfeto de carbono (CS2) / The use of 2-thiothiazolidine-4 carboxilic acid (TTCA) as a biomarker of carbon disulphide exposure

É apresentado uma revisão sobre as principais característicastoxicológicas do sulfeto de carbono. Baseando-se nestas informações é estabelecida a conduta mais adequada para a monitorização biológica da exposição ocupacional a este agente tóxico. Contasta-se que a avaliação do ácido 2 - tiotiazolidina - 4 carboxílico (TTCA) na urina é o biomarcador mais adequado.