Cochlear implants (CIs) provide sound and speech sensations for patients with severe to profound hearing loss by electrically stimulating the auditory nerve. While most CI users achieve some degree of open set word recognition under quiet conditions, hearing that utilizes complex neural coding  has proved elusive, probably because of the inability of CIs to create narrow regions of spectral activation. Several novel approaches have recently shown promise for improving spatial selectivity, but substantial design differences from conventional CIs will necessitate much additional safety and efficacy testing before clinical viability is established. Outside the cochlea, magnetic stimulation from small coils (micro-coils) has been shown to confine activation more narrowly than that from conventional microelectrodes, raising the possibility that coil-based stimulation of the cochlea could improve the spectral resolution of CIs. To explore this, we delivered magnetic stimulation from micro-coils to multiple locations of the cochlea and measured the spread of activation utilizing a multielectrode array inserted into the inferior colliculus; responses to magnetic stimulation were compared to analogous experiments with conventional microelectrodes as well as to responses when presenting auditory monotones. Encouragingly, the extent of activation with micro-coils was ~60% narrower compared to electric stimulation and largely similar to the spread arising from acoustic stimulation. The dynamic range of coils was more than three times larger than that of electrodes, further supporting a smaller spread of activation. While much additional testing is required, these results support the notion that magnetic micro-coil CIs can produce a larger number of independent spectral channels and may therefore improve auditory outcomes. Further, because coil-based devices are structurally similar to existing CIs, fewer impediments to clinical translational are likely to arise. More than 430 million people worldwide, ~5% of the world’s population, live with disabling hearing loss, making it the most common sensory deficit . The WorThe limitations in performance are thought to arise largely from the small number of independent spectral channels created by CIs. In contrast to the large number of independent channels arising from the ~30,000 SGNs in the intact human cochlea, CIs produce as few as 8–10 independent spectral channels . This isSeveral novel approaches are under consideration to increase the number of independent channels created by CIs. For example, the genetic insertion of light-sensitive ion channels into SGNs allows their activation to be controlled by light instead of electric fields, resulting in narrower channels . AnotherRecent studies have shown that magnetic stimulation from small, implantable coils, referred to as micro-coils, can effectively drive neurons of the central nervous system (CNS) while confining activation to a narrow region around each coil . A coil-Here, we investigate the ability of magnetic stimulation from bent-wire micro-coils to drive the auditory pathways. We evaluated the efficacy of stimulation and the resulting spectral spread of activation by recording with a multielectrode array positioned along the tonotopic axis of the inferior colliculus (IC), an auditory nucleus downstream from the cochlea and found in the midbrain. We show that bent-wire micro-coils can indeed drive auditory circuits effectively and further, that the resulting activation from single micro-coils is significantly narrower than that from traditional electrodes, that is, approaching the relatively narrow spread produced by acoustic stimuli. Control experiments verified that responses from coils were indeed magnetic in origin and that they did not arise from activation of hair cells. Taken together, our results suggest that further investigation of coil-based CIs is warranted as they may produce a larger number of independent spectral channels than electrode-based CIs and thus could lead to improved clinical outcomes.d′ (d-prime), was calculated to construct spatial tuning curves . The MUAs, which are combined responses from single-unit activities with various tuning curves, typically have ‘V’-shaped tuning curves  were 12, 9, and 5, respectively (indicated by white stars), which is consistent with the known tonotopic organization of the mouse IC  inferior colliculus (IC) in anesthetized mice . Multiung curves  and MUA-mouse IC . Only 5 mouse IC  and thusmouse IC .Consistent with previous studies, increases in suprathreshold sound pressure levels (SPLs) typically led to increases in the magnitude of the IC response before saturating at higher intensity levels . The dynAfter recording auditory brainstem response (ABR) and IC responses to acoustic stimulation , the cocFollowing confirmation of severe to profound sensorineural hearing loss on ABR testing, we measured IC responses to both magnetic or electric stimulation, delivered to both basal and apical cochlear. Prior to capturing IC responses, ABRs were recorded each time a coil or electrode was inserted (or reinserted) into the cochlea  to provide a relatively quick validation that a given surgical procedure had not damaged the early auditory pathways or the implant itself. ABRs to electric stimulation eABRs;  were genn = 6), the average characteristic frequency for BSs  at the stimulus amplitude for which the BS reached d′ levels of 2 and 4 (the red arrow in d′ level of 2) . The spatial spread, that is, the distance between the dorsal- and ventral-most responding electrodes , the spread of activation from electric stimulation was wider than that from magnetic stimulation  than for acoustic stimulation  but larger than that for electric stimulation  (The rate-level functions to magnetic and electric stimulation (measured at the BS) are shown in  0.0031) , suggest 0.0031) . Note th 0.0031) , suggestn = 2), responses to electric and magnetic stimulation in the basal turn were robust and spatial spread remained narrower in magnetic vs. electric stimulation ), eliminating the possibility that a broken coil might be activating neurons capacitively. The coils with DC resistance over 10 Ω were discarded. Third, measurements of the temperature change produced by coils were previously shown to be less than 1°C , greatlyTo compare the spread of activation across modalities, we quantified MUAs recorded at multiple sites along the tonotopic axis of IC and constructed STCs . The MUAs, which are combined responses from single-unit activities with various tuning curves, typically have ‘V’-shaped tuning curves  and MUA-, it is necessary to employ stronger stimulus amplitudes, thereby exacerbating the spread.Previous studies have reported that the spread of current from electrodes inserted into the scala tympani recruits SGNs across spatially extensive regions, thereby limiting the spectral specificity of artificial sound encoding . For exaIn contrast to the electric fields arising from electrodes, the spread of activation from coils measured here was significantly narrower. While our experiments do not identify the reasons for the lower spread, magnetic stimulation is known to have some intrinsic advantages over electrodes and electric stimulation. For example, the physics underlying the generation and spread of magnetic fields (Maxwell’s equations) ensures that the induced electric fields are confined to tight regions around the magnetic flux. In addition, the magnetic fields induced by the flow of electric current through coils are highly permeable to all biological materials and thus are relatively impervious to bone and other high-resistance materials within the cochlear environment. As a result, magnetic fields pass readily through the high-resistance bony wall of the scala tympani, without the need to increase stimulation amplitudes . Although magnetic fields are not thought to activate neurons directly, time-varying magnetic fields induce electric fields, and therefore magnetic fields ‘carry’ the electric field across the walls of the scala tympani where they can induce activation of SGN processes.In addition to the low spectral resolution associated with electric stimulation, the DR for encoding sound intensity is also limited. For example, the DR for listeners with normal hearing is approximately 120 dB while the DR for CI users is typically restricted to 10–20 dB . The smaOur measurements suggest that the DR for magnetic stimulation from micro-coils was approximately three times greater than that for electrical stimulation. It is likely that the gradual recruitment of SGNs with magnetic stimulation contributed to the wider DR. Further, the responses to magnetic stimulation were not saturated at the peak stimulus amplitudes we used here, suggesting the DR values reported here may be underestimated. The expanded DRs for magnetic stimulation provide additional support for the potential of micro-coil-based CIs to enhance the quality of CI-induced hearing.The ability to create narrow spectral channels with micro-coils, even in the tiny cochlea of the mouse, is encouraging as it suggests that coil-based stimulation has the potential to create a larger number of independent spectral channels in clinical use. Further, the relatively simple and compact bent-wire coils used here raise the possibility that CIs can be manufactured that are structurally similar to existing devices. This too is encouraging because such an approach raises fewer short- and long-term safety concerns. While much additional development and testing is needed, we believe that these findings clearly suggest that further investigation of coil-based stimulation of the cochlea is warranted.In this study, electric stimulation was delivered in a monopolar configuration. Other configurations, for example, bipolar, tripolar, and focused multipolar result in improved spatial selectivity in both animal models  and humaI2 × R power consumption of coil-based devices and thus compensates somewhat for the high current levels, supplied electric energy for a single magnetic ‘pulse’ (52 µJ) is still considerably higher than that for a single electrical biphasic pulse (245 nJ – based on 700 µA and 10 kΩ impedance). It is likely that power consumption in future micro-coil devices can be significantly improved using a number of changes that are relatively straightforward to implement. For example, the coil design used here was identical to that used for stimulation of cortex; tailoring the coil design to optimize SGN activation could potentially reduce power consumption by an order of magnitude or more  helps to reduce the  or more . In addiAnother potential concern would be the compatibility of implanted micro-coils with strong exogenous magnetic fields. A previous study has tested the effect of 1.5 T exogenous magnetic field on micro-coils and electric wire-based implants designed for deep brainstem stimulation . Their rIn the present study, it is likely that most SGNs were intact since our deafening procedure mainly targeted hair cells. Maintaining uniform survival of SGNs was essential to ensure accurate comparison of the spread of activation across modalities, however, this situation does not uniformly reflect the pathological conditions of all implanted patients. Patients typically receive CIs months or years after the onset of deafness and often have considerable SGN loss . Thus, iFinally, it will also be necessary to build and test devices that incorporate multiple coils to ensure that they can indeed be reliably developed and safely implanted as well as to determine the minimum separation for which coils remain independent. The ability to match the structure and mechanical properties of coil-based CIs will be highly beneficial as it will allow existing fabrication techniques and surgical procedures to be harnessed, thereby facilitating the transition into clinical practice.All procedures were approved by the Institutional Animal Care and Use Committee of Massachusetts Eye and Ear (protocol# 15-003), and carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals. CBA/CaJ mice were purchased from Jackson Laboratories or bred in house. Mice of either sex aged 6–16 weeks were used in the experiments. Experiments were conducted in an acoustically and electrically isolated walk-in chamber kept at 32–36°C. Mice were anesthetized for the duration of experiments with ketamine (100 mg/kg) and xylazine (10 mg/kg). Animals’ anesthesia level and heart rate were regularly monitored, and one-third of the initial ketamine/xylazine dose  was given as needed.The left cochlea was accessed surgically. A postauricular incision was made and the underlying tissue and musculature were dissected to expose the bulla. A bullotomy was performed by carefully rotating a 28 G needle and enlarging the hole with fine forceps to expose the round window. The left pinna with skin and tissue extending into the external auditory canal was cut and removed to expose the tympanic membrane. To access the contralateral inferior colliculus (IC), the postauricular incision was extended to over midline, and a craniotomy was made just caudal to the temporoparietal suture and to the contralateral side of the midline with a scalpel.After the original insertion into the inferior colliculus, the position of the multielectrode recording array was not repositioned while switching from one stimulus modality to the next . Due to the fragility of the recording electrode array, we took extra care to avoid disturbing the skull, as dislodgement of the array would have altered tonotopicity and thus weakened the ability to accurately compare spectral spread between trials.All stimuli were generated using LabVIEW and MATLAB software controlling custom-made system based on National Instruments 24-bit digital input/output boards.A custom acoustic system coupled to a probe tube was inserted into the external ear canal close to the tympanic membrane, with two miniature earphones  serving as sound sources. Acoustic stimuli were pure tone pips of 5-ms duration.Magnetic stimulation was presented using custom-made micro-coils , which are highly similar to ones used in previous studies for stimulation of other, noncochlear regions of the CNS . The coiOnce completed, the coil was removed and replaced with a micro-electrode so that an analogous series of electric stimulation experiments could be performed at the same location. Electric stimulation was delivered in a monopolar configuration. The stimulating electrode was a conical platinum–iridium tip with a resistance of 10 kΩ, a height of ~125 µm and a base diameter of 30 µm . An EMG needle was inserted into the neck muscle to serve as a return electrode. At least three individual electrodes with an identical design were tested. Like micro-coils, the stimulating electrodes were inserted through the round window  or via cochleostomy in the apical turn for intracochlear stimulation. Electric stimuli were also controlled by the same function generator used for magnetic stimulation. Stimulus waveforms were rectangular biphasic pulses with phase duration of 25 µs and no interphase interval. Stimulation amplitudes ranged from 0 to 1000 µA. The stimulus for each amplitude was repeated at least 39 times with a pulse rate of 25 pulses/s.Magnetic stimulation responses were assayed first in some animals, whereas electric stimulation responses were assayed first in other animals. The same placements were used for either the micro-coils or the electrodes. Experiments were terminated whenever the animal’s vital parameters, as measured by heart and respiratory rate, declined. The decline was typically observed at around 5–7 hr and preceded by a decline in inferior colliculus responses. A complete set of basal and apical stimulations were tested in two animals, a complete set of only basal stimulation were tested in four additional animals, and a complete set of only apical stimulation were tested in one additional animal.f1 and f2, with f2/f1 = 1.2 and f1 being 10 dB above f2) at half-octave steps from f2 = 5.66–45.25 kHz, and in 5 dB intensity increments from 10 to 80 dB SPL. DPOAE thresholds were defined as the f2 intensity required to generate a DP response of 10 dB SPL over noise floor. ABR responses to 5-ms tone pips were measured between subdermal electrodes , amplified 10,000 times and filtered through a 0.3–3.0 kHz band-pass filter. For each frequency, the sound level starting below the threshold was increased in 5 dB steps and 512 responses. ABR thresholds were defined as the lowest level at which a repeatable waveform could be visually detected.DPOAE and ABR were recorded as previously described . A custo2/site, center-to-center electrode spacing of 50 μm; NeuroNexus Technologies, Ann Arbor, MI; A1 × 16-3 mm-50-177). Recordings were collected at a sampling rate of 25 kHz and analyzed offline using custom-written MATLAB scripts. Neighboring neurons in the IC have similar spectrotemporal preferences, and therefore multiple neurons generate action potentials at a similar timing  Ther timing . (3) Ther timing . (4) Thed′ (d-prime) was calculated by comparing aMUAs across successive pairs of stimulus levels in each electrode  was determined from the minima of the d′ = 1 iso-contour. On average, the cumulative d′ levels of 2 and 4 correspond to 7.23 ± 5.34 and 18.53 ± 9.94 dB SPL above threshold for acoustic stimulation, 0.47 ± 0.30 and 1.41 ± 0.53 dB 1 mA above threshold for electric stimulation, and 2.57 ± 1.33 and 7.98 ± 5.41 dB 1 V above threshold for magnetic stimulation , comparing spatial spreads at a fixed dB level above threshold was not feasible. Alternatively, some studies measured spatial spreads at different dB levels above threshold for different modalities, for example 20 and 6 dB above threshold for acoustic and electric stimulation, respectively . More res of 2–4 . Thus, tall STCs –4A–D, comulation .d′ > 1). Using the characteristic frequency of each electrode obtained from the acoustic stimulation, the spatial spread could then be converted to the spectral spread of cochlear excitation, that is, the width of the corresponding frequency bands.The spatial spread of the response was calculated as the distance between the ventral- and dorsal-most electrodes exhibiting a suprathreshold response (d′ > 1) at the stimulus intensity that elicited a cumulative d′ value of 2.The spread of excitation was also evaluated by measuring the number of peaks observed in the ST profiles. The number of peaks was measured by the number of isolated electrode groups exhibiting a suprathreshold response  to images acquired at low magnification (×10 objective) on a fluorescent microscope . Cochlear whole mounts were subsequently imaged with a confocal microscope  using a ×63 glycerol-immersion objective (1.3 N.A.) at the 32-kHz cochlear frequency region. Inner hair cells per 100 µm were counted in the basal turn at 32, 45.25, and 64 kHz , both cochleae were extracted and processed as previously described . PFA wasd 64 kHz . This study demonstrates that microcoil magnetic stimulation in the cochlea generates efficient and spatially precise activation of the auditory system. This new method opens interesting possibilities to improve the resolution of auditory restoration by implanted devices. public reviews designed to be posted alongside the preprint for the benefit of readers; ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: i) Decision letter after peer review:eLife. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Barbara Shinn-Cunningham as the Senior Editor. The following individuals involved in the review of your submission have agreed to reveal their identity: Yann Nguyen (Reviewer #1); Tania Rinaldi Barkat (Reviewer #2).Thank you for submitting your article "Magnetic Stimulation Allows Focal Activation of the Mouse Cochlea" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1) Please answer all comments from the three referees, paying particular attention to the quantifications of the data. There are several figures which only show examples and thorough quantifications displaying the variability of the outcome should be added.More specifically:2) Quantification of the frequency response area FRA using the d' index is very puzzling should be complemented with more classical measures Q10dB, the Q40dB or the Octave distance which are classically used in auditory neuroscience.3) Quantification of the spectral spread of activation used in figure 4A-B must be improved. Based on the 11 animals tested with ipsilateral tones , the authors estimated that each electrode corresponds to a particular frequency, then the between-electrode distance is converted in an octave distance. This is an artificial, comparison of electrical and magnetic stimulation should be done based on electrode distance only.4) By using ipsilateral sounds instead of contralateral sounds, the authors largely underestimated the acoustic inputs reaching the recording sites (because the main ascending pathways cross the midline between the cochlear nucleus and the superior olivary complex). Further experiments should be performed with contralateral recordings.5). The Spatial Tuning Curves (STC) in the plots presented in Figure 1D,E,F are just classical Frequency Response Areas (FRA). FRA should be used instead of STC.6) Supplementary figure 1 should be carefully improved. The quality of the data seems questionable given the amplitude of Action Potential (AP). Also, based on this figure the mean aMUA display for acoustic stimulation has a long onset latency and the response peaks after 10 ms. This type of response has nothing in common with the classic phasic responses or the phasic-tonic responses of IC neurons published from PSTHs over the last three decades . The discrepancy should be discussed.7) The claim that activation triggered by acoustic stimulation is narrow is questionable. It has been known for decades that although some IC neurons have V-shaped frequency response areas (FRA) similar to those of primary auditory nerve fibers, others have substantially different shapes indicative of the interplay of excitation and inhibition in shaping these receptive fields . Thus, the selective V-shaped shown in Figure 1 at presentation of pure tone stimuli is clearly not representative of the diversity of IC neurons. In addition, among the neurons exhibiting V-shaped FRA, many have responses extending in both directions 2-4 octaves away from the characteristic frequency (CF). The sharp tuning of pure tone responses in IC at 80dB , is not fully compatible with the known physiological properties of these neurons. Similarly, the fact that the rate-level functions are monotonic as shown in Figure 1H is also totally incompatible with the known physiological properties of IC neurons . More examples of IC neurons response diversity should be given and the quantification of frequency tuning should not depend on 'V-shapeness'.Reviewer #1 (Recommendations for the authors):In conclusion, I think that this is a very original and interesting article because it addresses a major problem of cochlear implantation with a disruptive approach.If the comments in the Public Review could be answered, I will consider positively this work for a publication.Reviewer #2 (Recommendations for the authors):eLife articles have a large and diverse readership, it would be important to have this information in the paper instead of only referring to other published papers. A schematic comparing magnetic and electrical stimulation, for example, added as a panel to figure 2 (maybe to illustrate the description of l.266-275), could also address this.1) The introduction is really well written and has a lot of important and interesting information. It would, however, be helpful to also include a short paragraph on how the magnetic stimulation actually works. As 2) I am not sure what reason could explain that single action potentials could not be detected (l. 428). The recording electrodes have all the characteristics that should allow nice distinctions of action potentials. This should be discussed in more detail.3) Some results are only described in the text and not presented in figures . I would suggest to illustrated all results in figures, and having all results in the Results section, including the controls described on l.227-235.4) The mice used have a wide age range (6-16 weeks). Have you checked whether there is an age dependence on the results?5) An important aspect of the success – or not – of cochlear implants is, in addition to spatial spread and dynamic range, the temporal precision of the signal. It would be interesting to compare the timing of responses between magnetic and electrical stimulation. If the temporal precision is as high with magnetic as with electrical stimulation, then I think this approach would definitely represent an exciting improvement to classical cochlear implants.6) The results of Figure 4c are described differently in the Results section. It would be nice if the figure matches the description (as well as if it shows examples of peaks).7) In figure 1G, only 3 out of 11 mice have responses to 8 kHz. Is this because the frequency was not tested, or because the recording electrode was not in the 8 kHz region of the IC? If this was the case, how could that (mis)placement influence the results and interpretations of the magnetic and electrical stimulation?8) For Figure 4a, 4b, and 5c, a multiple comparison test would be more appropriate than a student t-test.Reviewer #3 (Recommendations for the authors):1. There are many basic notions regarding the auditory physiology that the authors should handle more carefully in the entire experiment.1a. Throughout the entire manuscript, the authors are talking about Spatial Tuning Curves (STC) but there is absolutely no spatial selectivity tested here. Spatial receptive fields correspond to situations where a set of calibrated speakers are placed at different azimuths or different elevations to test the spatial selectivity to pure tones or broadband noises . What is tested here is the spectral selectivity of IC neurons, and as it is tested throughout a range of intensity, the plots presented in figure 1D,E,F are just classical Frequency Response Areas (FRA) that have been classified for decades with robust and relevant parameters.1.b. In this paper, the FRA limits/borders are defined by the d' index sets at 1, 2 or 4, which does not tell anything about the tuning breadth. The FRA is classically used to determine the range of frequencies/intensities triggering significant responses above spontaneous firing rate and to know what is the value of firing rate reach at each intensity. Comparing pairs of stimulus levels for each electrode (methods line 445-446 for the explanation of the d') has no meaning. Detecting a difference between the average Multi-unit Activity (aMUA) tell you neither if there is a significant response, nor what is the strength of the response.1.c. In addition, the supplementary figure 1 that is supposed to display what represents the aMUA is very difficult to consider in a quality paper. I cannot recognize a Multi-Unit recording based on these traces because there is no Action Potential (AP) of correct amplitude visible on this figure. Based on this figure the mean aMUA display for acoustic stimulation has a long onset latency and the response peaks after 10 ms. This type of response has nothing in common with the classic phasic responses or the phasic-tonic responses of IC neurons published from PSTHs over the last three decades .1.d. The claim that activation triggered by acoustic stimulation is narrow is, at least, questionable. It has been know for decades that although some IC neurons have V-shaped frequency response areas (FRA) similar to those of primary auditory nerve fibers, others have substantially different shapes indicative of the interplay of excitation and inhibition in shaping these receptive fields . Thus, the selective V-shaped shown in Figure 1 at presentation of pure tone stimuli is clearly not representative of the diversity of IC neurons. In addition, among the neurons exhibiting V-shaped FRA, many have responses extending in both directions 2-4 octaves away from the characteristic frequency (CF). Thus, the idea conveyed in this paper that the tone response of IC neurons is narrow at 80dB , is just incompatible with the known physiological properties of these neurons. Similarly, the fact that the rate-level functions are monotonic as shown in Figure 1H is also totally incompatible with the known physiological properties of IC neurons . Essential revisions:1) Please answer all comments from the three referees, paying particular attention to the quantifications of the data. There are several figures which only show examples and thorough quantifications displaying the variability of the outcome should be added.eLife journal. We believe this will help the readers assess our results quantitatively.We appreciate the comments from the reviewers as well as the editor’s feedback and summary. All comments have been addressed and a summary of our responses is in this document; changes are tracked in the revised document. We have performed additional analysis for data quantification and provide explanation as to our rationale for choosing the analysis methods we used. We have also added more figures for ABR and IC responses in the figure supplements  and presented data points for individual samples in each plot. All source data used to make figures have been uploaded to the repository following the guideline of the More specifically:2) Quantification of the frequency response area FRA using the d' index is very puzzling should be complemented with more classical measures Q10dB, the Q40dB or the Octave distance which are classically used in auditory neuroscience.In general, we tried to use conventional methods so that readers can readily understand and interpret our results. We acknowledge that measuring the spread of activation at certain dB levels above threshold is commonly used to evaluate responses to acoustic stimulation. However, we felt that the use of the classic Q10dB or Q40dB measures to compare the spread of activation across different modalities was less suitable since each modality has a different dynamic range. For example, the dynamic range of electric stimulation was only ~ 3 dB, while that of acoustic stimulation was more than 20 dB. Therefore, we adopted an approach based on fixed significance of response strengths, i.e., measuring at an identical discrimination index. In this way, the estimation of the spread of excitation becomes independent of the stimulus’s nature and makes neural activation by different modalities more comparable. This approach is similar to that used in many previous studies in which new stimulation paradigms were evaluated  and thus allows the performance of micro-coils to be more easily compared. Nevertheless, we agree that providing more detailed explanations would be helpful to many readers and have added additional language in the Method section of the revised manuscript.[Line 528] “The value of d’ represents the distance between the means in units of a standard deviation – the larger the d’ value, the more separated the distributions are.”[Line 532] “To estimate the spread of activation from acoustic stimulation, previous studies measured the width of IC activation at a sound pressure level of 10 – 40 dB above threshold. However, given that dynamic ranges are significantly different across modalities , comparing spatial spreads at a fixed dB level above threshold was not feasible. Alternatively, some studies measured spatial spreads at different dB levels above threshold for different modalities., e.g., 20 dB and 6 dB above threshold for acoustic and electric stimulation, respectively . More recent studies that have evaluated novel stimulation modalities and compared them to acoustic and/or electric responses compared spatial spreads at a given response strength, typically at cumulative d’ values of 2-4 . Thus, to remain consistent with these previous studies, we also compared spectral spreads from acoustic, magnetic, and electric stimulation at cumulative discrimination indexes of 2 and 4.”d’ index with respect to dB levels above threshold for each modality  and added relevant descriptions in the Materials and methods section. We believe these will facilitate understanding of our results by readers, especially those who are accustomed to the analysis based on fixed dB levels.We have also plotted the cumulative [Line 550] “On average, the cumulative d′ levels of 2 and 4 correspond to 7.23 ± 5.34 and 18.53 ± 9.94 dB SPL above threshold for acoustic stimulation, 0.47 ± 0.30 and 1.41 ± 0.53 dB 1 mA above threshold for electric stimulation, and 2.57 ± 1.33 and 7.98 ± 5.41 dB 1 V above threshold for magnetic stimulation .”3) Quantification of the spectral spread of activation used in figure 4A-B must be improved. Based on the 11 animals tested with ipsilateral tones , the authors estimated that each electrode corresponds to a particular frequency, then the between-electrode distance is converted in an octave distance. This is an artifical, comparison of electrical and magnetic stimulation should be done based on electrode distance only.As the reviewer mentioned, we converted the distance of activated electrodes to octave distance based on the characteristic frequency of each electrode derived from Figure 2D. This translation provides an estimate of the activated frequency band across the tonotopic organization of the cochlea by stimulation and previous studies evaluating novel methods of artificial stimulation presented the spread of activation by artificial stimulation in a similar way . Therefore, we felt the use of this approach would provide the most direct comparison to previous work. Nevertheless, we agree that quantifying the activation spread by electrode distance would be more intuitive to some readers and have added the corresponding plots in Figure 5.4) By using ipsilateral sounds instead of contralateral sounds, the authors largely underestimated the acoustic inputs reaching the recording sites (because the main ascending pathways cross the midline between the cochlear nucleus and the superior olivary complex). Further experiments should be performed with contralateral recordings.We thank the reviewers for highlighting the anatomy of the auditory pathway and, specifically, its crossing over the midline. The wording in the original manuscript was confusing as all modes of stimulation  were delivered to the left cochlea and responses measured from the right inferior colliculus (IC); the side to which stimulation was delivered was referred to as ipsilateral and the opposite side was referred to as contralateral. We revised the wording as shown below and believe it will greatly reduce the potential for confusion.[Line 100] “We stimulated the left cochlea with acoustic, electric, and magnetic stimuli and measured responses from a 16-channel recording array implanted along the tonotopic axis of the right  inferior colliculus (IC) in anesthetized mice .”5). The Spatial Tuning Curves (STC) in the plots presented in Figure 1D,E,F are just classical Frequency Response Areas (FRA). FRA should be used instead of STC.IC responses can be presented by both frequency response areas (FRA) and spatial tuning curves (STC). FRA typically represents neuronal responses to different sound frequencies, recorded at a fixed site, while STC represents neuronal responses to acoustic stimulation with a fixed frequency or artificial stimulation at a fixed intracochlear location, recorded at multiple sites. FRA and STC constructed from the same data set are presented in Snyder et al., 2008. Although the patterns of FRA and STC are often similar in appearance, they serve different purposes; FRA conveys information about the excitatory/inhibitory circuits of auditory pathways and frequency tuning functions while STC visualizes the activity evoked across the tonotopic organization by stimulation at a fixed site (or fixed sound frequency). Because one of the main goals of our study was to compare the spread of activation across different stimulation modalities, we used STC, as was done in many previous studies .6) Supplementary figure 1 should be carefully improved. The quality of the data seems questionable given the amplitude of Action Potential (AP). Also, based on this figure the mean aMUA display for acoustic stimulation has a long onset latency and the response peaks after 10 ms. This type of response has nothing in common with the classic phasic responses or the phasic-tonic responses of IC neurons published from PSTHs over the last three decades . The discrepancy should be discussed.We acknowledge that there was a mistake in the amplitude unit and have corrected this in the revised manuscript (µV mV); we thank the Reviewers for their attention to detail. We suspect the latency differences arise from interspecies variability, i.e., previous studies that report peak onsets of 8-15 ms were not performed in mice. We point out that one previous study in mice  shows a peak latency of ~10 ms, similar to what we observe here. We again thank the reviewer for making us aware of reporting the incorrect amplitude.7) The claim that activation triggered by acoustic stimulation is narrow is questionable. It has been known for decades that although some IC neurons have V-shaped frequency response areas (FRA) similar to those of primary auditory nerve fibers, others have substantially different shapes indicative of the interplay of excitation and inhibition in shaping these receptive fields . Thus, the selective V-shaped shown in Figure 1 at presentation of pure tone stimuli is clearly not representative of the diversity of IC neurons. In addition, among the neurons exhibiting V-shaped FRA, many have responses extending in both directions 2-4 octaves away from the characteristic frequency (CF). The sharp tuning of pure tone responses in IC at 80dB , is not fully compatible with the known physiological properties of these neurons. Similarly, the fact that the rate-level functions are monotonic as shown in Figure 1H is also totally incompatible with the known physiological properties of IC neurons . More examples of IC neurons response diversity should be given and the quantification of frequency tuning should not depend on 'V-shapeness'.In the studies mentioned by the reviewer, IC single-units were classified as “V”, “I” , “O” (narrow tuning at threshold and no responses at suprathreshold) as well as other less-frequent types. All of these studies report single-unit FRAs to acoustic stimulation and neurons with “V-shaped” tuning curves were reported as the most abundant (Casseday and Covey 1992). In the present study, however, we recorded multiunit responses; combining responses from multiple types of single-units, as would occur with our multiunit recordings, are dominated by neurons with “V-shaped” with lesser contributions from other types, and almost certainly results in a V-shaped tuning curve . In addition, Figures 1D-F in the original figure set showed spatial tuning curves (STCs), not FRAs. The difference between STC and FRA is described in the answer for essential review Q5. The STCs based on IC multi-unit activities typically have narrow V-shaped curves . Thus, while we agree that  Figures 1D-F do not appear to be representative of single unit FRAs, we think they are representative of multi-unit STCs. We have added language to clarify this issue as follows:[Line 108] “The MUAs, which are combined responses from single-unit activities with various tuning curves, typically have “V” shaped tuning curves  and MUA-based STCs for acoustic stimulation also have narrow “V” shaped curves.”Reviewer #2 (Recommendations for the authors):1) The introduction is really well written and has a lot of important and interesting information. It would, however, be helpful to also include a short paragraph on how the magnetic stimulation actually works. As eLife articles have a large and diverse readership, it would be important to have this information in the paper instead of only referring to other published papers. A schematic comparing magnetic and electrical stimulation, for example, added as a panel to figure 2 (maybe to illustrate the description of l.266-275), could also address this.Thank you for the valuable suggestion. We added the following illustration in Figure 1.2) I am not sure what reason could explain that single action potentials could not be detected (l. 428). The recording electrodes have all the characteristics that should allow nice distinctions of action potentials. This should be discussed in more detail.This is also a valid point, and the following language has been added.[Line 497] “Neighboring neurons in the IC have similar spectro-temporal preferences, and therefore multiple neurons generate action potentials at a similar timing . This often leads to poor isolation of single-unit activity in IC recordings .”3) Some results are only described in the text and not presented in figures . I would suggest to illustrated all results in figures, and having all results in the Results section, including the controls described on l.227-235.Thanks for alerting us to this; appropriate modification has been made as follows.[Line 107 /121 (resubmitted manuscript)] We have indicated that the relevant data is shown in Figure 6D.[Line 172-176/186-190] We have added all STCs in the supplementary document .[Line 205/219] We used ABR and DPOAE as an “on-screen” evaluation for successful deafening. DPOAE amplitudes were completely flat. We have included more ABR data in the supplementary figure.[Line 227-233/247-251] We did not make a record for the impedance of insulation or the DC resistance of the coil leads. Instead, once a coil failed , the coil was discarded and recordings obtained from the coil were exempted from the analysis. We clarified this in the text.[Line 247]“If the impedance of the coil insulation was found to be less than 200 MΩ after an experiment, recordings obtained from the coil were exempted from the analysis.”[Line 250] “The coils with DC resistance over 10 Ω were discarded.”[Line 233-235/251-254] The temperature of the coils was measured in previous studies. We cited the relevant studies in the manuscript.4) The mice used have a wide age range (6-16 weeks). Have you checked whether there is an age dependence on the results?We intended to use young adult mice with good hearing  prior to deafening. In our cohort, we did not observe any differences attributable to age.5) An important aspect of the success – or not – of cochlear implants is, in addition to spatial spread and dynamic range, the temporal precision of the signal. It would be interesting to compare the timing of responses between magnetic and electrical stimulation. If the temporal precision is as high with magnetic as with electrical stimulation, then I think this approach would definitely represent an exciting improvement to classical cochlear implants.This is an important point. As the reviewer mentioned, one of the important goals of artificial stimulation is to evoke high rate auditory responses with high temporal precision. SGNs can follow a rate of auditory stimulation up to a few hundred Hz and maintain sub-millisecond precision of spike timing, which is crucial for auditory function . In this study, we delivered electric and magnetic stimulation with a pulse rate of 25 Hz. Although there was no significant change in response probability and timing across pulses, this pulse rate is too low to assess temporal fidelity. We are very interested in the temporal kinetics of auditory responses to magnetic stimulation and will report our findings in future studies.6) The results of Figure 4c are described differently in the Results section. It would be nice if the figure matches the description (as well as if it shows examples of peaks).We thank the reviewer for pointing this out. We have added the number of STCs in each group in Figure 5E so that the figure matches the description.7) In figure 1G, only 3 out of 11 mice have responses to 8 kHz. Is this because the frequency was not tested, or because the recording electrode was not in the 8 kHz region of the IC? If this was the case, how could that (mis)placement influence the results and interpretations of the magnetic and electrical stimulation?Responses to 8 kHz were tested in every animal. The fact that only 3 mice have responses to 8 kHz likely results from the positioning of the recording probe, i.e., positioning missed the IC region that responds best to that frequency. The 8 kHz is a fairly low characteristic frequency that would be expected to be represented toward the apex of the cochlea. Nevertheless, responses to electric and magnetic stimulation always had the best electrodes clearly within the range of the recording probe . Thus, we consider this issue to be a minor one, but added the following sentence to the Results.[Line 111] “Only 5 out of 11 animals had best sites at 8 kHz  and thus the sampling of the lowest-frequency region of the IC may have been incomplete”.8) For Figure 4a, 4b, and 5c, a multiple comparison test would be more appropriate than a student t-test.Thank you for alerting us to this. We have analyzed the data with multiple independent variables with ANOVA  while maintaining a student t-test for the data with a single independent variable.Reviewer #3 (Recommendations for the authors):1. There are many basic notions regarding the auditory physiology that the authors should handle more carefully in the entire experiment.1a. Throughout the entire manuscript, the authors are talking about Spatial Tuning Curves (STC) but there is absolutely no spatial selectivity tested here. Spatial receptive fields correspond to situations where a set of calibrated speakers are placed at different azimuths or different elevations to test the spatial selectivity to pure tones or broadband noises . What is tested here is the spectral selectivity of IC neurons, and as it is tested throughout a range of intensity, the plots presented in figure 1D,E,F are just classical Frequency Response Areas (FRA) that have been classified for decades with robust and relevant parameters.This comment is addressed in the Essential revisions section (Q5).1.b. In this paper, the FRA limits/borders are defined by the d' index sets at 1, 2 or 4, which does not tell anything about the tuning breadth. The FRA is classically used to determine the range of frequencies/intensities triggering significant responses above spontaneous firing rate and to know what is the value of firing rate reach at each intensity. Comparing pairs of stimulus levels for each electrode (methods line 445-446 for the explanation of the d') has no meaning. Detecting a difference between the average Multi-unit Activity (aMUA) tell you neither if there is a significant response, nor what is the strength of the response.The difference between FRA and STC is explained in the Essential revisions section (Q5).d’ value was calculated by comparing aMUAs across successive pairs of stimulus levels, but then accumulated up to each stimulus intensity to calculate the cumulative d’ value. The cumulative d’ value essentially provides a comparison between responses to each stimulus level and spontaneous activities. Thus, the contour lines based on the cumulative d’ index indicate the range of IC electrodes and stimulus intensities where significant responses above spontaneous activity were observed. Our approach is also consistent with many previous studies which assessed the spread of activation of new stimulation strategies. Nevertheless, we thought that it would be helpful to provide more detailed explanations. Please see the answer for the Essential revisions Q2.As the reviewer understood, the 1.c. In addition, the supplementary figure 1 that is supposed to display what represents the aMUA is very difficult to consider in a quality paper. I cannot recognize a Multi-Unit recording based on these traces because there is no Action Potential (AP) of correct amplitude visible on this figure. Based on this figure the mean aMUA display for acoustic stimulation has a long onset latency and the response peaks after 10 ms. This type of response has nothing in common with the classic phasic responses or the phasic-tonic responses of IC neurons published from PSTHs over the last three decades .This comment is addressed in the Essential revisions section (Q6).1.d. The claim that activation triggered by acoustic stimulation is narrow is, at least, questionable. It has been know for decades that although some IC neurons have V-shaped frequency response areas (FRA) similar to those of primary auditory nerve fibers, others have substantially different shapes indicative of the interplay of excitation and inhibition in shaping these receptive fields . Thus, the selective V-shaped shown in Figure 1 at presentation of pure tone stimuli is clearly not representative of the diversity of IC neurons. In addition, among the neurons exhibiting V-shaped FRA, many have responses extending in both directions 2-4 octaves away from the characteristic frequency (CF). Thus, the idea conveyed in this paper that the tone response of IC neurons is narrow at 80dB , is just incompatible with the known physiological properties of these neurons. Similarly, the fact that the rate-level functions are monotonic as shown in Figure 1H is also totally incompatible with the known physiological properties of IC neurons .This comment is addressed in the Essential revisions section (Q7).


COVID-19 disease, caused by SARS-CoV-2 virus, first emerged as a presentation of severe respiratory disease in 2019. Although children exhibit mild disease, concerns were raised about serious infection in immunocompromised children. The current national guidance recommends that immunocompromised children between 12 and 18 years of age should be offered three primary doses of the Pfizer BioNTech vaccine, 8 weeks apart, followed by a booster dose within 3 months. This audit looked at the awareness and uptake of this regime in young persons on immunosuppression. This information was disseminated to families during clinical contacts and automatic replies sent out from the team mailbox.To collect the data for the audit, we used an anonymous questionnaire to capture the following information:• Diagnosis• Immunomodulatory/Immunosuppressive treatment• Their awareness of the regime for COVID vaccine • Number of vaccines taken• If not taken, why?The questionnaires were handed out to 31 patients attending Paediatric Rheumatology day-care and outpatient clinics over a two-week period for their response. There were no non-responders. Patients who were not on any immunosuppressant medication were excluded.The split of their diagnoses and medications are summarised in Patients with JIA (55%) unsurprisingly dominated the cohort, followed by JSLE, JDM and scleroderma. Only 3/31 patients (10%) were on any form of systemic steroid therapy . Majority of the patients (21/31 – 68%) were on Methotrexate, either on its own, or in combination with one of the biologic agents (one scleroderma patient was on MTX + MMF). 14/21 (45%) patients were on one of the biologic agents, of which only one patient was on Rituximab.The results showed that only 6/31 (19%) of patients/their carers knew the correct number (3 + 1) of COVID vaccines recommended in this cohort. 18/31 (58%) patients had received the vaccine, of which 4 patients refused further doses due to side effects they had experienced following the first dose. Of the 13 young people who did not take the vaccine, 9 patients (29%) were unsure whether they need the vaccine. They did not know the benefits of the vaccine and were afraid it either could have a negative effect on immunocompromised children or just were not aware of the guidelines. The other 4 (13%) participants did not want to take the vaccine due to their own personal beliefs.Although concerns were raised about serious COVID-19 infection in immunocompromised children, there is currently very little evidence to suggest that the infection rate and severity of COVID-19 infection in children treated with Methotrexate or biologic agents is higher or the treatment needs to be discontinued or the doses adjusted. There is some emerging evidence to suggest that adults on Rituximab and to a lesser extend Mycophenolate may have increased risk of developing severe outcomes from COVID-19, which has not been replicated in children. The recommendation for third primary dose is based on preliminary results from UK studies of real-world vaccine effectiveness (VE) in persons who are immunosuppressed, suggesting a modest reduction in VE against symptomatic COVID-19. There is also emerging evidence that COVID vaccination significantly reduces the risk of Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) in 12 – 18 year olds.Despite the notion that the team had disseminated information on the vaccine regime to patients, only one fifth of the patients/carers knew the exact regime for COVID vaccine recommended in this group of young people.Just under 60% of the patients took the vaccine, with the rest choosing not to have it due to a mixture of lack of information and personal choice.The action plan was drawn up to:1. enquire about and document vaccination status, and provide advice and information during every clinical contact;2. include COVID vaccine in education sessions by nursing team;3. include the information as default in all clinic letters;4. reaudit in six months.


The coronavirus disease 2019 (COVID-19) pandemic exposed the risks of poorly controlled noncommunicable diseases, especially in persons with diabetes. The pandemic outbreak in Cape Town, South Africa, required a rapid reorganisation of primary care services. Community-based measures were activated to ensure continuity of care by implementing home delivery of medication by community health workers. After five months of de-escalated chronic care, observations at an urban primary care facility suggested that noncommunicable disease patients had not overtly decompensated despite suspending regular in-facility services. This study attempted to understand what impact de-escalation of regular care and escalation of community-based interventions had on type 2 diabetes patients at this primary care facility.A mixed methods study design was used, consisting of data captured prospectively from diabetic patients who returned to the facility for routine care post-lockdown, as well as qualitative interviews to ascertain patients’ experiences of the home delivery service.p < 0.01), although this may be because of confounding factors. The mean glycaemic control was suboptimal both at baseline and post-lockdown in both groups. Interviews with 83 study patients confirmed the acceptability of the home delivery intervention.The data set included 331 (72%) patients in the home delivery group and 130 (28%) in the non-home delivery group. Regression analysis demonstrated a statistically significant relationship between home delivery and improved diabetic control (The rapid reorganisation of primary care services illustrates the versatility of a functional community-oriented primary care service, although not fully developed yet, to adapt to emerging community healthcare needs in the pandemic era. Approximately 82% of patients attending Cape Town PCFs have at least one chronic condition,4 limiting the capacity to provide care for other emergent conditions in overcrowded PCFs that are often understaffed.The coronavirus disease 2019 (COVID-19 or C-19) pandemic exposed the risks associated with poor noncommunicable disease (NCD) control, particularly amongst diabetics,5 Overcrowding led to a further concern that high-risk NCD patients, many of whom are elderly, would be exposed to C-19 when attending PCFs. Routine nonemergency PCF services in Cape Town, including scheduled chronic care visits, were therefore de-escalated, and community-based interventions were implemented.6 Primary care facilities headcounts were reduced and only some outpatient services were continued on a ‘see and treat’ (S&T) basis.The outbreak of C-19 in the Western Cape (WC) province in March 2020, therefore, required rapid reorganisation of PCF-based services to allow for physical distancing within facilities and to increase capacity for the anticipated influx of patients requiring acute care.7 Prepackaged medication from the WC’s central Chronic Dispensing Unit (CDU) was delivered to patients’ homes without requiring the usual PCF-based clinical assessments. Community health workers screened patients for C-19 symptoms and other complaints in the community and referred them to PCFs only when necessary. These measures are aligned with the community-orientated primary care (COPC) approach that has been adopted by the WC’s Department of Health (WCDOH) as the cornerstone of a re-engineered primary health care (PHC) system.8Home delivery of medication (HDM) by community health workers (CHWs) was implemented as a community-based measure to ensure ongoing NCD patient care.9 Whilst the reduction in trauma cases could be ascribed directly to lockdown regulations such as a curfew and the ban on alcohol sales, the reasons for reduced nontrauma cases are less clear. These figures are aligned with other evidence from this period. A Cape Town district hospital study reported a 43% reduction in trauma cases and a 33% reduction in nontrauma cases over five weeks of lockdown compared to the same period pre-lockdown.10 The HPCHC team also noted that NCD patients had not overtly decompensated despite the suspension of regular in-facility services. It was also noted that fewer NCD-related emergencies presented to HPCHC in this period. The many potentially confounding factors notwithstanding, we hypothesised that some NCD patients may have benefited from the HDM service and that control of NCDs may have stabilised or even improved despite the suspension of facility-based care.After five months of de-escalated NCD care (April–August 2020), shifts in service utilisation and clinical presentation patterns were reported by clinical team members based at one of the WCDOH PCFs, Hanover Park Community Health Centre (HPCHC). Overall, the emergency centre (EC) visits at HPCHC decreased by 36% over five months of lockdown in 2020, with similar reductions in trauma and nontrauma cases.We sought to test this hypothesis by selecting a T2D study cohort as a proxy for the NCD population based on the following: (1) the high prevalence of T2D in the community, (2) the convenience of measuring T2D outcomes objectively with haemoglobin A1c (HbA1c) measurements and (3) the importance of glycaemic control in relation to C-19 risk. We aimed to determine the impact of de-escalated NCD care on T2D control in HPCHC patients by determining (1) if de-escalation was associated with any change in standard-of-care measures, including glycaemic control as reflected by HbA1c levels in T2D patients returning to routine PCF-based care; (2) whether HDM by CHWs improved disease control (as assessed by standard-of-care observations); and (3) whether patients receiving HDM (a) support this intervention and want it to continue, (b) feel that it improved their self-management during the intervention period and (c) supported the expansion of the service to include clinical monitoring and referral to PCFs as needed.11 Quantitative data (standard-of-care observations) were first collected and analysed, followed by the collection and analysis of qualitative data to help explain or elaborate the quantitative results – the rationale being that quantitative data provide a general understanding of the problem, whereas qualitative data refine and explain statistically determined results by exploring participants’ views in more detail.We employed a two-phase mixed methods explanatory design.12Hanover Park Community Health Centre is one of the 51 PCFs in Cape Town. It provides comprehensive primary care to a community of approximately 50 000 people. Situated on the Cape Flats on the outskirts of Cape Town, the community is characterised by high levels of poverty, unemployment and gang-related crime. Before the pandemic, HPCHC had an average of 15 000 patient visits per month. Services include a routine outpatient department, clinics for NCDs, HIV, tuberculosis (TB) and mental health, an Emergencies Unit for medical emergencies and trauma, a Midwife Obstetric Unit (MOU) for antenatal, obstetrics and postnatal care, and allied medical services. In the pre-COVID era, the standard of care for stable NCD patients included repeat prescriptions for up to six months, coupled with clinical assessments by clinical nurse practitioners (CNPs) or medical officers (MOs), depending on the patient’s condition. Hanover Park Community Health Centre treats approximately 2600 diabetic patients annually, over 90% of whom have T2D.13 The balance of NCD patients was issued with 12-month CDU prescriptions based on a temporary departure from the legal maximum of six months for items not exceeding Schedule 5.14 Almost all T2D patients returning to HPCHC for routine NCD care during the study period were eligible. Eligibility criteria were as follows: an existing diagnosis of T2D and the inclusion of metformin and/or glimepiride on their CDU prescriptions during the lockdown period. These patients formed the quantitative data set.The study cohort comprised T2D patients returning to HPCHC for routine care from 01 September 2020 when lockdown restrictions were lifted. Hanover Park Community Health Centre pharmacy data showed that 71% of NCD patients had been issued with standard 6-month CDU prescriptions without clinical assessments during the lockdown period, and they were due to return to the clinic for assessment and repeat prescriptions within the study period.With the start of the second C-19 wave in mid-December 2020, all non-emergency care (other than the S&T service) was again suspended. The study proceeded with the database that had been developed up to that point, and further study-related activities were completed remotely.A standardised data collection sheet was used to capture standard-of-care observations in Microsoft Excel. Standard-of-care data and results of blood tests were extracted from the folders of eligible T2D patients returning to HPCHC between 01 September 2020 and 15 December 2020. Data included HbA1c levels on the day of the visit and from before the pandemic  to evaluate and compare glycaemic control before the first wave of C-19 and after the lockdown period. Consultation data on the day of return were also collected and captured. Data collection by HPCHC clinical staff members occurred during consultations  and was therefore dependent on operational factors. Additional data collected from pre- and post-lockdown visits included dates of visits, age, gender, weight, height (if available), blood pressure (BP) and pre-lockdown creatine levels to determine baseline kidney function (estimated glomerular filtration rate [eGFR]), HDM by a CHW during the lockdown, EC or hospital admissions during the lockdown period and confirmed (laboratory) diagnoses of COVID-19. Results of blood tests performed on the day of return were retrieved and included when they became available on the National Health Laboratory Service (NHLS) website.A survey questionnaire was developed to determine patients’ experiences and preferences regarding HDM, their level of understanding regarding de-escalation of care, the impact of HDM and their preferences regarding future care options, including HDM. The questionnaire was developed by the principal investigator (PI), assisted by two not-for-profit organisation (NPO) nurse supervisors who coordinated the HDM service. The questionnaire, piloted with 10 HDM recipients, contained open-ended questions to allow for free-text responses and Likert scale questions. Pilot data were not included in our analysis. The questionnaire was subsequently refined by the study team to allow for optimal implementation. Every fifth patient in the quantitative data set was invited to complete the qualitative questionnaire if they met three additional criteria: (1) initial data extracted from the patient’s folder were complete, (2) a pre-lockdown HbA1c level had been taken within 12 months of the first lockdown and (3) the patient had received HDM during the lockdown period. Patients not meeting these criteria were excluded in favour of the next qualifying patient. On this basis, patients were selected for interview by the PI and research assistant (RA). Patient information leaflets and informed consent documents were available in the three main languages spoken in the WC. Consenting and interviews were initially conducted in person in a private room at the facility by the RA and subsequently telephonically because of the second lockdown.15 cleaned, analysed and shared with the study team in online meetings. Preliminary trend analysis was performed during the study by the data analysts together with the PI, and the final data set was reviewed by the whole study team. The hard copies of the data set (folder extracts) were numbered to correspond with the Excel spreadsheet and stored in a secure location. Following descriptive statistics to summarise the study sample data, we performed bivariate analysis to explore pairwise correlations between the variables of interest related to the study objectives (including comparing HDM and non-HDM groups), as well as multivariate analysis to analyse these relationships in more detail.Quantitative data were periodically submitted to Percept Actuaries and Consultants for data analytic support. The data were exported to Stata 16 software,16 The data from the questionnaire were grouped to highlight the participants’ understanding of the de-escalation of routine services, the impact of the HDM service and their preferences.Qualitative interview responses were captured on RedCap and exported to Excel, cleaned and inductively coded manually and independently by two RAs with experience in qualitative data analysis.This study was approved by the University of Cape Town’s Human Research Ethics Committee (ref. no. 480/2020) and the Western Cape Provincial Health Research Committee to conduct the research onsite.17 The average time difference between the baseline and follow-up HbA1c measures was 1.3 years (480 days) for the whole cohort (HDM and non-HDM patients). Eighty-three interviews with HDM patients (58 in-person and 25 telephonic) had been completed by the end of the data collection phase of the study, between 03 November 2020 and 23 March 2021.Around 861 patients with T2D returned to HPCHC for routine care between 01 September and 15 December 2020 (between the first and second waves of C-19). Of this cohort, standardised data collection sheets were completed for 521 adult patients. When reviewing the standard-of-care data set for completeness, data for 64 patients had to be excluded see : 44 becaThe number of individuals excluded adds up to 64; however, one of these individuals had no home delivery status specified and had missing HbA1c measures, and three individuals had both missing HbA1c measures and were duplicate observations. Therefore, they had more than one exclusion criterion.Multivariate analysis  shows thp < 0.01). Other statistically significant differences in this regression were age, high BP and weight. The relationship between HbA1c and age was nonlinear. As expected, high BP also had a positive relationship with HbA1c: clients with high BP on average had 0.517% higher HbA1c levels compared to those not classified as having high BP. Unexpectedly, weight had a statistically significant, inverse relationship with HbA1c, probably because of confounding factors that were not controlled for.For the whole study population, the HbA1c measures for the HDM group were 0.464% lower than in the non-HDM group, which is highly statistically significant  regression were gender and weight. Women had, on average, 0.308% higher HbA1c measures than men in the well-controlled sample. The relationship between weight and HbA1c is in the expected direction; a 1 kg increase in weight is associated with a 0.01% increase in HbA1c.The mean HbA1c level for the whole T2D cohort reflected poor pre-lockdown diabetic control on average at 9.44%, with a 0.25% overall increment to 9.69% post-lockdown. This finding did not support our initial hypothesis. Notwithstanding, there are significant differences within the larger group that indicate different levels of control. The baseline pre-lockdown glycaemic control for the HDM cohort was better than that of the non-HDM cohort, with a mean HbA1c level of 9.3% versus 9.6%. This may reflect more favourable baseline conditions or a greater level of clinical stability even before HDM was implemented. However, the increment in the HbA1c level for the HDM group was 0.2% versus 0.5% for the non-HDM group. The disaggregation of the well-controlled patients (HbA1c < 7.5%) from the larger group shows that they comprised 28.0% of the HDM group pre-lockdown and 27.0% post-lockdown. The well-controlled proportion of the non-HDM group, on the other hand, was 27.0% pre-lockdown and 22.0% post-lockdown, representing a five times greater loss of well-controlled patients from the non-HDM group. In addition, although the overall incidence of laboratory-confirmed C-19 in this group of patients was small , the incidence in the non-HDM group  was proportionately higher than that of the HDM group . This difference is not significant because of the small sample size. The headline findings  are summarised in i]t is very difficult for me to walk to the clinic – when I do go, I have to borrow a wheelchair from a neighbour for a fee’ .The second study objective was to understand the experience of patients who were receiving HDM from the CHWs. The survey questionnaire was used to determine patient preferences with regard to receiving medication and chronic care – specifically where and how they would like to receive care in future. All participants (100%) expressed a clear preference for receiving HDM versus collecting medication at the clinic. Most patients (53%) cited convenience as the number one reason for wanting to receive medication by home delivery, followed by safety concerns, transportation challenges, and mobility (23%). Increased stress because of PCF overcrowding and long waiting times, as well as possible infection risks (12%), were also cited as reasons not to collect medication from the clinic. One patient cited difficulty accessing the clinic, noting not only the convenience of HDM but also how it saved on additional cost: ‘ to collect my medication, but they are not always available, so I really prefer home delivery.’ ‘I will have to send my daughters to the civic [Whilst the convenience of having a collection site closer to home might mitigate challenges such as waiting times and the cost of transportation, it does not address the additional needs of physically challenged patients, or others who have conditions or responsibilities such as paid work that may need an after-hours service.Most (94%) participants support receiving clinical care at home or at a support site within the community. When asked if they were able to manage their diabetes better if supported by CHWs who would refer them to the clinic, if necessary, 93% ‘agreed’ or ‘strongly agreed’ with this statement. However, 62% of this cohort showed a deterioration in their follow-up HbA1c levels. Some patients indicated that not having access to a glucometer was challenging and that the service could be improved should the CHWs have blood glucose tests available during their visits. Responses indicate that the service received from the CHW was generally better. Individualised care allowed them to spend more time with the CHW and ask questions that were related to other health challenges in the family, in addition to their chronic conditions. Participants also cited the experience as less stressful. Those who were at work and therefore did not interact with CHWs noted that the service was more convenient as they did not have to take a day off work just to collect medication. Overall, patients showed a strong preference for home delivery, as it mitigated some of the challenges that they faced when accessing their chronic medication in general and more specifically during the pandemic.Based on the qualitative assessments of 83 HDM recipients from this database, it can be concluded that a CHW intervention is a highly acceptable and desirable healthcare component. The HDM service has fostered increased trust in the assistance that CHWs can provide. The headline findings from the interviews were as follows:All patients understood the need for clinic visits to be suspended because of C-19 and all felt that HDM worked well, primarily because they received reminders from CHWs to take their medication.Most patients felt that their blood glucose levels were better but did not attribute this to the HDM service directly.All patients wanted to continue with the HDM programme, either to save time and avoid exposure to the coronavirus at the clinic or because of safety concerns.Most patients indicated that the support from the CHW or nurse helped them to manage their diabetes better.This study aimed to assess the impact of de-escalated in-facility services on patients with NCDs who received care at an urban PCF during the first lockdown period necessitated by the C-19 pandemic in 2020. Amongst the measures adopted to ensure uninterrupted NCD management, CHWs were deployed to deliver chronic medication to patients’ homes, enabling them to remain at home. When patients were permitted to return to the facility for review during a period of re-escalated in-facility care after the first wave had settled, standard-of-care folder extracts were obtained on 461 patients with T2D. This cohort of NCD patients was assessed to determine changes in disease control as well as any potential benefits that could be ascribed to the HDM service. Quantitative outcomes for the whole cohort were assessed and a qualitative survey review of patients receiving HDM was performed as part of a mixed methods study design. This study provided a unique opportunity to assess the status of patients who were temporarily denied access to their usual facility-based care but whose contact with CHWs was increased to maintain their stability and prevent clinical decompensation.18 The evidence in this cohort of returning T2D patients suggests that the strategy of de-escalated NCD care was largely successful, at least amongst those patients who received HDM. On average, HDM was positively associated with better glycaemic control when compared with patients not receiving HDM. The regression analysis demonstrated a statistically significant relationship between HDM and diabetic control (p < 0.01), although this may also be circumstantial and because of unintended selection bias at baseline. However, the greater retention of well-controlled patients in the HDM group is significant, as both groups had very similar proportions at baseline, with mean HbA1cs of 6.53% (HDM) versus 6.56% (non-HDM). Although there was a 0.03% difference, these cohorts were both optimally controlled for covariates, and it is, therefore, less likely that social or clinical circumstances impacting diabetic control would have applied to either group at baseline. In this sense, HDM was the most significant variable and was positively associated with good glycaemic control. Home delivery of medication may also have been protective against exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as intended, with a higher incidence of C-19 in the non-HDM group (3.1% vs 1.8%), although the overall incidence was low in both groups, and the sample size was too small to determine any statistical significance.The quantitative analysis revealed that 72% of the cohort had received HDM during the lockdown period, whilst 28% had continued, for various reasons, to collect their medication from the facility. This proportion is aligned with the overall HDM project data in the greater Cape Town metropole, showing a 71.4% delivery rate in 42 participating facilities.19 This is broadly indicative of a system-wide and well-documented lack of effective control of NCDs such as T2D and hypertension at PCFs in Cape Town.20 These findings are consistent with other evidence throughout the country. In 2012, Amod reported that two-thirds of diabetic patients in South Africa had HbA1c levels above 7.5%,21 and in a recently published study, Piotie et al. showed that amongst diabetic patients on the chronic medication programme in Tshwane, only 29.2% achieved control, although this study used an HbA1c cut-off of 7.0% to determine control based on the 2017 Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines.22It should be noted that baseline HbA1c levels for the whole cohort indicate poor glycaemic control, with a mean pre-lockdown level of 9.44% increasing to 9.69% post-lockdown. These levels are aligned with the long-term averages for the facility  that show only 28.0% of patients have controlled levels of 6.0% – 8.0%, whilst 24.0% have levels of 8.0% – 10.0% and 41.0% have levels over 10.0%.23 Empowerment is developed across these areas by elements of patient care that have been shown to be deficient or absent in PCFs, particularly in relation to NCDs.24 Based on the interview responses, it is highly likely that the three empowerment domains had improved amongst HDM recipients, although this was not necessarily associated with improved control. Sustained lower glycaemic levels will also require improvements in pharmacological management, particularly relating to the use of insulin.The qualitative assessments of patients receiving HDM showed a strong preference for the continuation of this service. There was also a broad expression of support for the clinical role that was played by the CHWs who provided the HDM service, with most patients describing their experience of HDM as better and less stressful than it would have been at the clinic. It is also interesting to note that many interviewed patients perceived their disease control to have improved during the lockdown period and felt that the support they received from the CHWs had helped them to manage their diabetes better, even though quantitatively 62% of these respondents had increased HbA1c levels post-lockdown. These patients were likely reflecting empowerment elements that they had developed in their interactions with the CHWs. Three patient empowerment domains are described in the literature: (1) patient activation, (2) patient self-management capacity and (3) psychosocial self-efficacy .17 Patients on oral therapy are disadvantaged as they are not provided with glucometers and test strips, and very few can afford independent monitoring. As a result, most diabetic patients have no day-to-day knowledge of their glucose readings and are therefore less likely to pro-actively improve their glycaemic control. The problem is aggravated when primary care clinicians are reluctant to initiate insulin because of a lack of confidence in their own and their patient’s ability to manage insulin treatment.25 In addition, patients who are initiated on insulin according to PACK guidelines26 are prescribed dosages that are often subtherapeutic (e.g. < 0.1/kg per day), to titrate the dose upwards in conjunction with a self-monitoring diary. However, patients commonly fail to self-monitor effectively because of a lack of health education. Their prescriptions may then be repeated with insulin dosages that remain inadequate.The Diabetes Data Cascade for Hanover Park, prepared by the Provincial Health Data Centre, shows that only 35% of patients are provided with insulin and oral therapy, whilst 57% are on oral agents only.27 Many initiatives have demonstrated the positive impact of CHW involvement in diabetic care as well as the cost-effectiveness of these interventions.28 However, there is little evidence available relating to the unique role that CHWs performed during a lockdown period – itself an unprecedented event. In the context described in this study, CHWs were required to ensure that patients were provided with their chronic medication by HDM and to act as the ‘eyes and ears’ of the health system by screening for any problems that might require escalation of care. In a healthcare service that remains predominantly facility-based and where implementation barriers have persisted since COPC was officially introduced in 2017 (in WC), the lockdown forced the use of a desired COPC model of service. In retrospect, the C-19 pandemic has allowed healthcare to leapfrog several obstacles in the COPC implementation process. To some extent, this in turn has made it possible for the researchers to assess the impact of the model during the lockdown period through the lens of the HDM service.Notwithstanding the need to improve pharmacological management, the HDM initiative is well aligned with the commitment of the National Department of Health and the WCDOH to move towards a COPC approach to improve health services and save costs.29 A combination of diabetogenic factors is evident, including poor dietary practices beginning in early childhood, often linked to socio-economics, and a food economy that promotes the consumption of cheap calories in the form of sugar and related processed food products rather than healthy alternatives. In addition, opportunities for physical exercise are restricted and the outdoor environment is frequently unsafe. Against this background, NCD patients are highly dependent on medication for control, and adherence is an important predictor of a positive long-term outcome.30 This study demonstrates that HDM, in at least ensuring a continuing supply of medication, may have resolved one potential barrier to adherence, that is, access to medication even when routine clinical services are de-escalated. It is equally important, however, that pharmacological management and patient empowerment elements are optimised to improve outcomes of NCD care and that of any other chronic condition. To this end, a novel approach to care may be possible by leveraging lessons learnt through our telemedicine experience during the pandemic.31 A project is currently being undertaken at HPCHC to provide remote support for poorly controlled diabetics via a telemedicine doctor and to link these patients with CHWs when required.32 Western Cape Government Health (WCDOH) is also piloting an e-locker system at several facilities for selected patients who are provided with a code via short message service (SMS) that will allow them to retrieve their medication at their convenience within a specified time period. Innovations of this nature are not only clinically indicated but are also critical to ensure that diabetic care is economically viable.In the community context of the HPCHC service area, as in much of the Cape Flats, the adult prevalence of T2D has reached crisis proportions. Erasmus et al. found a prevalence of 28.2% in a comparable local population versus a pooled national prevalence of 15.25% in South African adults over 25 years of age.33 most of which are preventable by improving glycaemic control. Compounding this problem is the small proportion of T2D patients in South Africa who are diagnosed and treated. In the public sector, which provides care to 85% of the population, there are a mere 240 000 diabetic patients in care, representing only 5.2% of diabetic cases in SA, and 60.0% – 70.0% of these patients are not controlled. It is therefore likely that the direct costs of treating diabetes complications are significantly higher as a result of emergency care provided to undiagnosed patients.34 The authors of the COI study conclude that effective implementation of primary prevention, as well as secondary prevention in the form of targeted screening and improved pharmacological management of T2D, is urgent and must be prioritised. The valuable role of CHWs in the HDM service is indicative of the potential to achieve this goal by leveraging the advances that have been made to improve outcomes for patients receiving chronic disease management. The critical need to improve clinical outcomes in T2D is highlighted by the increasing prevalence of micro- and macrovascular disease complications and the well-established link between these and poor glycaemic control.35According to a 2019 cost-of-illness (COI) study, 49% of public sector spending on diabetes is related to managing complications,28 Based on the current CHW remuneration of R3500 per month, this could be achieved at a cost for every DALY averted of R6096. The World Health Organization considers an averted DALY cost-effective at any point below per capita gross domestic product (GDP). At 8.0% of GDP; this intervention would not only be highly cost-effective but would also remain so at a far higher CHW salary level. In combination with the WCDOH’s existing community-based wellness initiative known as WoW! (Western Cape on Wellness), which has demonstrated a significant impact amongst participants,36 a CHW intervention would be well-placed to achieve the essential change in the NCD landscape that is so urgently required.Daviaud et al. have conservatively estimated that a CHW intervention in diabetic screening and management will increase the diagnosis rate by 7.0% and control by 7.0%, which would add 6.9 years of life expectancy and avert almost 1.2 million disability-adjusted life years (DALYs) over 10 years.The results of this study suggest that there is a unique opportunity available in the aftermath of the pandemic to effectively improve diabetic control  by harnessing the advantages that have been demonstrated by the HDM service and combining these with improved pharmacological management, particularly relating to the introduction and titration of insulin. Not only would this provide a natural bridge between facility-based and community-based services, but it would also open the door to other innovative strategies, such as the telemedicine initiatives, that have emerged during the pandemic.This study was limited by several factors, including the difficulty of performing in-person research during the pandemic. This was only possible in the brief window period between the end of the first wave and the start of the second wave, when the clinic closed for nonemergency care for the second time. Data collection was prematurely discontinued; only the data set available at that point could be used for analysis, and a switch to telephonic interviews was required for the remaining qualifying patients. Selection bias may have played a role in the finding that HDM was positively associated with improved glycaemic control because the baseline (pre-lockdown) levels of the HDM group are slightly better than the non-HDM group (9.3% vs 9.6%). This may reflect factors that were not assessed in this study, such as differing socio-economic circumstances. This is an initial exploratory study at a single facility and is limited by potential confounding factors. As such, the results may not represent the regional or national situation. A follow-up study using a more detailed questionnaire has been carried out in four PCFs in the Cape Town metropolitan area. This will determine a wider range of indicators and experiences of NCD patients during the lockdown periods and may address limitations identified in this study.The emergence of the COVID-19 pandemic required a rapid response to the challenge of managing patients with pre-existing chronic conditions. This included de-escalating routine PCF-based NCD care to community-based care to reduce the risk of exposure to C-19. The results of this study show a statistically significant positive association between glycaemic control and a HDM intervention in T2D patients returning to the facility after the first lockdown. The intervention was highly valued by participants. Their responses also reflect elements of patient empowerment and self-management capacity linked to the supportive role played by CHWs in this period. Poor baseline levels of glycaemic control suggest serious system-wide challenges requiring innovative disease-management strategies to improve outcomes. Further research is required to identify such strategies and services.