5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries. Matching probabilities are higher when donors and patients share the same ethnic background, making it desirable to increase the diversity of the global donor pool by recruiting donors in new regions. Here, we report the establishment and the first 5 years of operation of the first unrelated stem cell donor center in Chile, a high-income country in South America with a population of over 19 million. Methods: We used online and in-person donor recruitment practices through patient appeals and donor drives in companies, universities, the armed forces, and public services. After confirmatory typing donors were subjected to medical work-up and cleared for donation. Results: We recruited almost 170,000 donors in 5 years. There were 1,488 requests received for confirmatory typing and donor availability checks, of which 333 resulted in medical work-up, leading to 194 stem cell collections. Products were shipped to Chile (48.5%) and abroad. Even when the COVID-19 pandemic challenged our activities, the number of donors recruited and shipped stem cell products remained steady. In Chile there was an almost 8-fold increase in unrelated donor transplantation activity from 16 procedures in 2016-2018 to 124 procedures in 2019-2021, mainly for pediatric patients following the center's establishment. We estimate that 49.6% of Chilean patients would find at least one matched unrelated donor in the global DKMS donor pool. Discussion: Establishing a DKMS donor center in Chile has significantly increased donor availability for Chilean patients and contributed to an increase of unrelated donor stem cell transplant activity.

HLA allele and haplotype frequencies of registered stem cell donors in Chile.

Patients in need of hematopoietic stem cell transplantation often rely on unrelated stem cell donors matched in certain human leukocyte antigen (HLA) genes. Donor search is complicated by the extensive allelic variability of the HLA system. Therefore, large registries of potential donors are maintained in many countries worldwide. Population-specific HLA characteristics determine the registry benefits for patients and also the need for further regional donor recruitment. In this work, we analyzed HLA allele and haplotype frequencies of donors of DKMS Chile, the first Chilean donor registry, with self-assessed "non-Indigenous" (n=92,788) and "Mapuche" (n=1,993) ancestry. We identified HLA alleles that were distinctly more abundant in the Chilean subpopulations than in worldwide reference populations, four of them particularly characteristic for the Mapuche subpopulation, namely B*39:09g, B*35:09, DRB1*04:07g, and DRB1*16:02g. Both population subsamples carried haplotypes of both Native American and European origin at high frequencies, reflecting Chile's complex history of admixture and immigration. Matching probability analysis revealed limited benefits for Chilean patients (both non-Indigenous and Mapuche) from donor registries of non-Chilean donors, thus indicating a need for ongoing significant donor recruitment efforts in Chile.

Immunogenetics in stem cell donor registry work: The DKMS example (Part 2).

DKMS is a leading stem cell donor registry with more than 9 million donors. Donor registry activities share many touch points with topics from immunogenetics or population genetics. In this two-part review article, we deal with these aspects of donor registry work by using the example of DKMS. In the second part of the review, we focus on donor typing of non-HLA genes, the impact of donor age, gender and CMV serostatus on donation probabilities, the identification of novel HLA, KIR and MIC alleles by high-throughput donor typing, the activities of the Collaborative Biobank and pharmacogenetics in the donor registry context.

Immunogenetics in stem cell donor registry work: The DKMS example (Part 1).

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.

Invisible Flashes Alter Perceived Sound Location.

Information integration across the senses is fundamental for effective interactions with our environment. The extent to which signals from different senses can interact in the absence of awareness is controversial. Combining the spatial ventriloquist illusion and dynamic continuous flash suppression (dCFS), we investigated in a series of two experiments whether visual signals that observers do not consciously perceive can influence spatial perception of sounds. Importantly, dCFS obliterated visual awareness only on a fraction of trials allowing us to compare spatial ventriloquism for physically identical flashes that were judged as visible or invisible. Our results show a stronger ventriloquist effect for visible than invisible flashes. Critically, a robust ventriloquist effect emerged also for invisible flashes even when participants were at chance when locating the flash. Collectively, our findings demonstrate that signals that we are not aware of in one sensory modality can alter spatial perception of signals in another sensory modality.

Simulation shows that HLA-matched stem cell donors can remain unidentified in donor searches.

The heterogeneous nature of HLA information in real-life stem cell donor registries may hamper unrelated donor searches. It is even possible that fully HLA-matched donors with incomplete HLA information are not identified. In our simulation study, we estimated the probability of these unnecessarily failed donor searches. For that purpose, we carried out donor searches in several virtual donor registries. The registries differed by size, composition with respect to HLA typing levels, and genetic diversity. When up to three virtual HLA typing requests were allowed within donor searches, the share of unnecessarily failed donor searches ranged from 1.19% to 4.13%, thus indicating that non-identification of completely HLA-matched stem cell donors is a problem of practical relevance. The following donor registry characteristics were positively correlated with the share of unnecessarily failed donor searches: large registry size, high genetic diversity, and, most strongly correlated, large fraction of registered donors with incomplete HLA typing. Increasing the number of virtual HLA typing requests within donor searches up to ten had a smaller effect. It follows that the problem of donor non-identification can be substantially reduced by complete high-resolution HLA typing of potential donors.

Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus.

PURPOSE: Clinical effects of repetitive transcranial magnetic stimulation (rTMS) in chronic tinnitus are moderate. More precise coil localisation strategies, innovative stimulation protocols, and identification of predictors for treatment response were proposed as promising attempts to enhance treatment efficacy. In this pilot study we investigated neuronavigated continuous theta burst TMS (cTBS). METHODS: Twenty-three patients received neuronavigated cTBS over the left primary auditory cortex in a randomized sham-controlled trial (verum = 12; sham = 11). Treatment response was evaluated with tinnitus questionnaires and numeric rating scales. Immediate change in numeric rating scales during the first session was used as predictor for treatment response. RESULTS: Tinnitus was significantly reduced after treatment, but there were no superior effects between verum vs. sham treatment. Immediate change in the first treatment session predicted the response to treatment only in the verum group. CONCLUSIONS: In our study, verum cTBS was not superior to sham which highlights the persistent need for improving non-invasive brain stimulation techniques for the treatment of tinnitus. Future research should focus on the transfer of positive single session effects to daily treatment trials.

Detecting tones in complex auditory scenes.

In everyday life, our auditory system is bombarded with many signals in complex auditory scenes. Limited processing capacities allow only a fraction of these signals to enter perceptual awareness. This magnetoencephalography (MEG) study used informational masking to identify the neural mechanisms that enable auditory awareness. On each trial, participants indicated whether they detected a pair of sequentially presented tones (i.e., the target) that were embedded within a multi-tone background. We analysed MEG activity for 'hits' and 'misses', separately for the first and second tones within a target pair. Comparing physically identical stimuli that were detected or missed provided insights into the neural processes underlying auditory awareness. While the first tone within a target elicited a stronger early P50m on hit trials, only the second tone evoked a negativity at 150 ms, which may index segregation of the tone pair from the multi-tone background. Notably, a later sustained deflection peaking around 300 and 500 ms (P300m) was the only component that was significantly amplified for both tones, when they were detected pointing towards its key role in perceptual awareness. Additional Dynamic Causal Modelling analyses indicated that the negativity at 150 ms underlying auditory stream segregation is mediated predominantly via changes in intrinsic connectivity within auditory cortices. By contrast, the later P300m response as a signature of perceptual awareness relies on interactions between parietal and auditory cortices. In conclusion, our results suggest that successful detection and hence auditory awareness of a two-tone pair within complex auditory scenes relies on recurrent processing between auditory and higher-order parietal cortices.

A spatially collocated sound thrusts a flash into awareness.

To interact effectively with the environment the brain integrates signals from multiple senses. It is currently unclear to what extent spatial information can be integrated across different senses in the absence of awareness. Combining dynamic continuous flash suppression (CFS) and spatial audiovisual stimulation, the current study investigated whether a sound facilitates a concurrent visual flash to elude flash suppression and enter perceptual awareness depending on audiovisual spatial congruency. Our results demonstrate that a concurrent sound boosts unaware visual signals into perceptual awareness. Critically, this process depended on the spatial congruency of the auditory and visual signals pointing towards low level mechanisms of audiovisual integration. Moreover, the concurrent sound biased the reported location of the flash as a function of flash visibility. The spatial bias of sounds on reported flash location was strongest for flashes that were judged invisible. Our results suggest that multisensory integration is a critical mechanism that enables signals to enter conscious perception.

Functional near-infrared spectroscopy to probe state- and trait-like conditions in chronic tinnitus: a proof-of-principle study.

OBJECTIVE: Several neuroscience tools showed the involvement of auditory cortex in chronic tinnitus. In this proof-of-principle study we probed the capability of functional near-infrared spectroscopy (fNIRS) for the measurement of brain oxygenation in auditory cortex in dependence from chronic tinnitus and from intervention with transcranial magnetic stimulation. METHODS: Twenty-three patients received continuous theta burst stimulation over the left primary auditory cortex in a randomized sham-controlled neuronavigated trial (verum = 12; placebo = 11). Before and after treatment, sound-evoked brain oxygenation in temporal areas was measured with fNIRS. Brain oxygenation was measured once in healthy controls (n = 12). RESULTS: Sound-evoked activity in right temporal areas was increased in the patients in contrast to healthy controls. Left-sided temporal activity under the stimulated area changed over the course of the trial; high baseline oxygenation was reduced and vice versa. CONCLUSIONS: By demonstrating that rTMS interacts with auditory evoked brain activity, our results confirm earlier electrophysiological findings and indicate the sensitivity of fNIRS for detecting rTMS induced changes in brain activity. Moreover, our findings of trait- and state-related oxygenation changes indicate the potential of fNIRS for the investigation of tinnitus pathophysiology and treatment response.

Steady-state responses in MEG demonstrate information integration within but not across the auditory and visual senses.

To form a unified percept of our environment, the human brain integrates information within and across the senses. This MEG study investigated interactions within and between sensory modalities using a frequency analysis of steady-state responses that are elicited time-locked to periodically modulated stimuli. Critically, in the frequency domain, interactions between sensory signals are indexed by crossmodulation terms (i.e. the sums and differences of the fundamental frequencies). The 3 × 2 factorial design, manipulated (1) modality: auditory, visual or audiovisual (2) steady-state modulation: the auditory and visual signals were modulated only in one sensory feature (e.g. visual gratings modulated in luminance at 6 Hz) or in two features (e.g. tones modulated in frequency at 40 Hz & amplitude at 0.2 Hz). This design enabled us to investigate crossmodulation frequencies that are elicited when two stimulus features are modulated concurrently (i) in one sensory modality or (ii) in auditory and visual modalities. In support of within-modality integration, we reliably identified crossmodulation frequencies when two stimulus features in one sensory modality were modulated at different frequencies. In contrast, no crossmodulation frequencies were identified when information needed to be combined from auditory and visual modalities. The absence of audiovisual crossmodulation frequencies suggests that the previously reported audiovisual interactions in primary sensory areas may mediate low level spatiotemporal coincidence detection that is prominent for stimulus transients but less relevant for sustained SSR responses. In conclusion, our results indicate that information in SSRs is integrated over multiple time scales within but not across sensory modalities at the primary cortical level.