Neuronal representation of sound source location in the auditory cortex during active navigation

The ability to localize sounds is crucial for the survival of both predators as well as prey. The former rely on their senses to lead them to the latter, which in turn also benefit from locating a predator in the vicinity to escape accordingly. In such cases, the sound localization process typically takes place while the animals are in motion. Since the cues that the brain uses to localize sounds are head-centered (egocentric), they can change very rapidly when an animal moves and rotates. This constitutes an even bigger challenge than sound localization in a static environment. Up to now, however, both aspects have mostly been studied separately in neuroscience, thus limiting our understanding of active sound localization during navigation. This thesis reports on the development of a novel behavioral paradigm – the Sensory Island Task (SIT) – to promote sound localization during unrestricted motion. By attributing a different behavioral meaning (associated to different outcomes) to two spatially separated sound sources, Mongolian gerbils (Meriones unguiculatus) were trained to forage for an area (target island) in the arena that triggered a change in the active sound source to the target loudspeaker and to report its detection by remaining within the island for a duration of 6 s. Importantly, the two loudspeakers played identical sounds and the location of the target island in the arena was changed randomly every trial. When the probability of successfully identifying the target island exceeded the chance level, a tetrode bundle was implanted in the primary auditory cortex of the gerbils to record neuronal responses during task performance. Canonically, the auditory cortex (AC) is described as possessing neurons with a broad hemispheric tuning. Nonetheless, context and behavioral state have been shown to modulate the neuronal responses in the AC. The experiments described in this thesis demonstrate the existence of a large variety of additional, previously unreported (or underreported) spatial tuning types. In particular, neurons that were sensitive to the midline and, most intriguingly, neurons that were sensitive to the task identity of the active loudspeaker were observed. The latter comprise neurons that were spatially tuned to only one of the two loudspeakers, neurons that exhibited a large difference in the preferred egocentric sound-source location for the two loudspeakers as well as spatially untuned neurons whose firing rate changed depending on the active loudspeaker. Additionally, temporal complexity in the neuronal responses was observed, with neurons changing their preferred egocentric sound-source location throughout their response to a sound. Corroborating earlier studies, also here it was found that the task-specific choice of the animal was reflected in the neuronal responses. Specifically, the neuronal firing rate decreased before the animal successfully finished a trial in comparison to situations in which the gerbil incorrectly left the target island before trial completion. Furthermore, the differential behavioral meaning between the two loudspeakers was found to be represented in the neuronal tuning acuity, with neurons being more sharply tuned to sounds coming from the target than from the background loudspeaker. Lastly, by implementing an artificial neural network, all of the observed phenomena could be studied in a common framework, enabling a better and more comprehensive understanding of the computational relevance of the diversity of observed neuronal responses. Strikingly, the algorithm was capable of predicting not only the egocentric sound-source location but also which sound source was active – both with high accuracy. Taken together, the results presented in this thesis suggest the existence of an interlaced coding of egocentric and allocentric information in the neurons of the primary auditory cortex. These novel findings thus contribute towards a better understanding of how sound sources are perceptually stable during self-motion, an effect that could be advantageous for selective hearing

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research