Cholinergic modulation in the vertebrate auditory pathway.

Acetylcholine (ACh) is a prevalent neurotransmitter throughout the nervous system. In the brain, ACh is widely regarded as a potent neuromodulator. In neurons, ACh signals are conferred through a variety of receptors that influence a broad range of neurophysiological phenomena such as transmitter release or membrane excitability. In sensory circuitry, ACh modifies neural responses to stimuli and coordinates the activity of neurons across multiple levels of processing. These factors enable individual neurons or entire circuits to rapidly adapt to the dynamics of complex sensory stimuli, underscoring an essential role for ACh in sensory processing. In the auditory system, histological evidence shows that acetylcholine receptors (AChRs) are expressed at virtually every level of the ascending auditory pathway. Despite its apparent ubiquity in auditory circuitry, investigation of the roles of this cholinergic network has been mainly focused on the inner ear or forebrain structures, while less attention has been directed at regions between the cochlear nuclei and midbrain. In this review, we highlight what is known about cholinergic function throughout the auditory system from the ear to the cortex, but with a particular emphasis on brainstem and midbrain auditory centers. We will focus on receptor expression, mechanisms of modulation, and the functional implications of ACh for sound processing, with the broad goal of providing an overview of a newly emerging view of impactful cholinergic modulation throughout the auditory pathway.

Healthy environments for athleTes (HEAT): environmental conditions along a 90 km ultra-marathon event, South Africa.

This paper provides an overview of the HEAT (Healthy Environments for AthleTes) project, which aims to understand the impact of environmental conditions on athlete health and performance during major sporting events such as long-distance running, cycling, and triathlons. In collaboration with the SAFER (Strategies to reduce Adverse medical events For the ExerciseR) initiative, the HEAT project carried out a field campaign at the 2022 Comrades Marathon in the KwaZulu-Natal province of South Africa. The measurement campaign deployed seven weather stations, seven PM2.5 monitors and one spore trap along the 90 km route to capture spatially representative measurements of complex micro-climates, allergenic aerospora, and particulate matter exposure. The results indicate that runners were exposed to moderate risk heat stress conditions. Novel findings from this initial campaign shows elevated and potentially harmful PM2.5 levels at spectator areas, possibly coinciding with small fire events around the race day festivities. Our findings show values PM2.5 levels over the WHO 24-h guidelines at all stations, while 2000 µg/m3 at two stations. However, the lack of an acute exposure standard means direct health impacts cannot be quantified in the context of a sport event. The HEAT project highlights important aspects of race day monitoring; regional scale climatology has an impact on the race day conditions, the microclimatic conditions (pollution and meteorology) are not necessarily captured by proximity instruments and direct environmental measurements are required to accurately capture conditions along the route.

A Developmental Switch in Cholinergic Mechanisms of Modulation in the Medial Nucleus of the Trapezoid Body.

The medial nucleus of the trapezoid body (MNTB) has been intensively investigated as a primary source of inhibition in brainstem auditory circuitry. MNTB-derived inhibition plays a critical role in the computation of sound location, as temporal features of sounds are precisely conveyed through the calyx of Held/MNTB synapse. In adult gerbils, cholinergic signaling influences sound-evoked responses of MNTB neurons via nicotinic acetylcholine receptors (nAChRs; Zhang et al., 2021) establishing a modulatory role for cholinergic input to this nucleus. However, the cellular mechanisms through which acetylcholine (ACh) mediates this modulation in the MNTB remain obscure. To investigate these mechanisms, we used whole-cell current and voltage-clamp recordings to examine cholinergic physiology in MNTB neurons from Mongolian gerbils (Meriones unguiculatus) of both sexes. Membrane excitability was assessed in brain slices, in pre-hearing (postnatal days 9-13) and post-hearing onset (P18-20) MNTB neurons during bath application of agonists and antagonists of nicotinic (nAChRs) and muscarinic receptors (mAChRs). Muscarinic activation induced a potent increase in excitability most prominently prior to hearing onset with nAChR modulation emerging at later time points. Pharmacological manipulations further demonstrated that the voltage-gated K+ channel KCNQ (Kv7) is the downstream effector of mAChR activation that impacts excitability early in development. Cholinergic modulation of Kv7 reduces outward K+ conductance and depolarizes resting membrane potential. Immunolabeling revealed expression of Kv7 channels as well as mAChRs containing M1 and M3 subunits. Together, our results suggest that mAChR modulation is prominent but transient in the developing MNTB and that cholinergic modulation functions to shape auditory circuit development.

Birth-weight centile at term and school performance at 12 years of age: linked cohort study.

OBJECTIVE: Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate-for-gestational age. The aim of this study was to evaluate the associations between birth-weight centile and intellectual development in term/near-term infants across the entire birth-weight spectrum, in order to provide a basis for better understanding of the long-term implications of fetal growth restriction and reduced placental function. METHODS: This was a population-based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003-2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016-2019. Regression analyses were conducted to assess the association of birth-weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501-550, and proportion of children who reached higher secondary school level. RESULTS: Mean school performance score increased gradually with increasing birth-weight centile, from 533.6 in the 1st -5th birth-weight-centile group to 536.8 in the 81st -85th birth-weight-centile group. Likewise, the proportion of children at higher secondary school level increased with birth-weight centile, from 43% to 57%. Compared with the 81st -85th birth-weight-centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth-weight-centile groups below the 80th centile, after adjusting for confounding factors. CONCLUSIONS: Birth-weight centile is associated positively with school performance at 12 years of age across the entire birth-weight spectrum, well beyond the conventional and arbitrary cut-offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short- and long-term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis.

OBJECTIVE: Anti-tuberculosis (antiTB) drugs are characterized by an important inter-interindividual pharmacokinetic variability poorly predictable from individual patients' characteristics. Therapeutic drug monitoring (TDM) may therefore be beneficial for patients with Mycobacterium tuberculosis infection, especially for the management of multidrug/extensively drug resistant- (MDR/XDR)-TB. Our objective was to develop robust HPLC-MS/MS methods for plasma quantification of 15 antiTB drugs and 2 metabolites, namely rifampicin, isoniazid plus N-acetyl-isoniazid, pyrazinamide, ethambutol (the conventional quadritherapy for susceptible TB) as well as combination of agents against MDR/XDR-TB: bedaquiline, clofazimine, delamanid and its metabolite M1, levofloxacin, linezolid, moxifloxacin, pretomanid, rifabutin, rifapentine, sutezolid, and cycloserine. METHODS: Plasma protein precipitation was used for all analytes except cycloserine, which was analyzed separately after derivatization with benzoyl chloride. AntiTB quadritherapy drugs (Pool1) were separated by Hydrophilic Interaction Liquid Chromatography (column Xbridge BEH Amide, 2.1 × 150 mm, 2.5 µm, Waters®) while MDR/XDR-TB agents (Pool 2) and cycloserine (as benzoyl derivative) were analyzed by reverse phase chromatography on a column XSelect HSS T3, 2.1 × 75 mm, 3.5 µm (Waters®). All runs last <7 min. Quantification was performed by selected reaction monitoring electrospray tandem mass spectrometry, using stable isotopically labelled internal standards. RESULTS: The method covers the clinically relevant plasma levels and was extensively validated based on FDA recommendations, with intra- and inter-assay precision (CV) < 15% over the validated ranges. Application of the method is illustrated by examples of TDM for two patients treated for drug-susceptible- and MDR-TB. CONCLUSION: Such convenient extraction methods and the use of stable isotope-labelled drugs as internal standards provide an accurate and precise quantification of plasma concentrations of all major clinically-used antiTB drugs regimens and is optimally suited for clinically efficient TDM against tuberculosis.

Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

Challenges and opportunities in academic neurosurgery.

Clinical academia aims to bridge the gap between clinicians and scientists, by combining academic activity with clinical practice. The term 'clinical academics' generally refers to clinicians who have protected time within their job plans for undertaking academic activities. Engagement with academic activity by trainees is not only essential to fulfil necessary curriculum competencies, but also allows them to explore areas of interest outside of clinical practice and develop advanced academic skills. This article provides an overview of different routes into academic neurosurgery, and discusses the advantages and difficulties in pursuing this career path. It also covers the differences between postgraduate research degrees and explores the different job plan models available at consultant level. Academic neurosurgery is a rewarding career and opportunities should be made available to those who wish to explore it further. Developing academic careers may have a positive impact on wider workforce planning strategies and improve the delivery of high-quality evidence-based neurosurgical care.

Multiple Sources of Cholinergic Input to the Superior Olivary Complex.

The superior olivary complex (SOC) is a major computation center in the brainstem auditory system. Despite previous reports of high expression levels of cholinergic receptors in the SOC, few studies have addressed the functional role of acetylcholine in the region. The source of the cholinergic innervation is unknown for all but one of the nuclei of the SOC, limiting our understanding of cholinergic modulation. The medial nucleus of the trapezoid body, a key inhibitory link in monaural and binaural circuits, receives cholinergic input from other SOC nuclei and also from the pontomesencephalic tegmentum. Here, we investigate whether these same regions are sources of cholinergic input to other SOC nuclei. We also investigate whether individual cholinergic cells can send collateral projections bilaterally (i.e., into both SOCs), as has been shown at other levels of the subcortical auditory system. We injected retrograde tract tracers into the SOC in gerbils, then identified retrogradely-labeled cells that were also immunolabeled for choline acetyltransferase, a marker for cholinergic cells. We found that both the SOC and the pontomesencephalic tegmentum (PMT) send cholinergic projections into the SOC, and these projections appear to innervate all major SOC nuclei. We also observed a small cholinergic projection into the SOC from the lateral paragigantocellular nucleus of the reticular formation. These various sources likely serve different functions; e.g., the PMT has been associated with things such as arousal and sensory gating whereas the SOC may provide feedback more closely tuned to specific auditory stimuli. Further, individual cholinergic neurons in each of these regions can send branching projections into both SOCs. Such projections present an opportunity for cholinergic modulation to be coordinated across the auditory brainstem.

Endogenous Cholinergic Signaling Modulates Sound-Evoked Responses of the Medial Nucleus of the Trapezoid Body.

The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. Happe and Morley (2004) discovered prominent expression of α7 nAChRs in rat SOC, suggesting possible engagement of ACh-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation have never been physiologically demonstrated. We probed nicotinic cholinergic influences on acoustic responses of MNTB neurons from adult gerbils (Meriones unguiculatus) of either sex. We recorded tone-evoked MNTB single-neuron activity in vivo using extracellular single-unit recording. Piggyback multibarrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, α7 and α4ß2. We observed that tone-evoked responses are dependent on ACh modulation by both nAChR subtypes. Spontaneous activity was not affected by antagonist application. Functionally, we demonstrate that ACh contributes to sustaining high discharge rates and enhances signal encoding efficacy. Additionally, we report anatomic evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.SIGNIFICANCE STATEMENT This study is the first to physiologically probe how acetylcholine, a pervasive neuromodulator in the brain, influences the encoding of acoustic information by the medial nucleus of trapezoid body, the most prominent source of inhibition in brainstem sound-localization circuitry. We demonstrate that this cholinergic input enhances neural discrimination of tones from noise stimuli, which may contribute to processing important acoustic signals, such as speech. Additionally, we describe novel anatomic projections providing cholinergic input to the MNTB. Together, these findings shed new light on the contribution of neuromodulation to fundamental computational processes in auditory brainstem circuitry and to a more holistic understanding of modulatory influences in sensory processing.

Validation and clinical application of a multiplex high performance liquid chromatography - tandem mass spectrometry assay for the monitoring of plasma concentrations of 12 antibiotics in patients with severe bacterial infections.

OBJECTIVE: Unpredictable pharmacokinetics of antibiotics in patients with life-threatening bacterial infections is associated with drug under- or overdosing. Therapeutic drug monitoring (TDM) may guide dosing adjustment aimed at maximizing antibacterial efficacy and minimizing toxicity. Rapid and accurate analytical methods are key for real-time TDM. Our objective was to develop a robust high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) for multiplex quantification of plasma concentrations of 12 antibiotics: imipenem/cilastatin, meropenem, ertapenem, cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam, amoxicillin, flucloxacillin, rifampicin, daptomycin. METHODS: A single extraction procedure consisting in methanol plasma protein precipitation and H2O dilution was used for all analytes. After chromatographic separation on an Acquity UPLC HSS-T3 2.1 × 50 mm, 1.8 µm (Waters®) column, quantification was performed by electro-spray ionisation-triple quadrupole mass spectrometry with selected reaction monitoring detection. Antibiotics were divided in two pools of calibration according to the frequency of analyses requests in the hospital routine antibiotic TDM program. Stable isotopically-labelled analogues were used as internal standards. A single analytical run lasted less than 9 min. RESULTS: The method was validated based on FDA recommendations, including assessment of extraction yield (96-113.8%), matrix effects, and analytical recovery (86.3-99.6%). The method was sensitive (lower limits of quantification 0.02-0.5 µg/mL), accurate (intra/inter-assay bias -11.3 to +12.7%) and precise (intra/inter-assay CVs 2.1-11.5%) over the clinically relevant plasma concentration ranges (upper limits of quantification 20-160 µg/mL). The application of the TDM assay was illustrated with clinical cases that highlight the impact on patients' management of an analytical assay providing information with short turn-around time on antibiotic plasma concentration. CONCLUSION: This simple, robust high-throughput multiplex HPLC-MS/MS assay for simultaneous quantification of plasma concentrations of 12 daily used antibiotics is optimally suited for clinically efficient real-time TDM.

A review of flux identification methods for models of sedimentation.

Most models of sedimentation contain the nonlinear hindered-settling flux function. If one assumes ideal conditions and no compression, then there exist several theoretically possible ways of identifying a large portion of the flux function from only one experiment by means of formulas derived from the theory of solutions of partial differential equations. Previously used identification methods and recently published such, which are based on utilizing conical vessels or centrifuges, are reviewed and compared with synthetic data (simulated experiments). This means that the identification methods are evaluated from a theoretical viewpoint without experimental errors or difficulties. The main contribution of the recent methods reviewed is that they, in theory, can identify a large portion of the flux function from a single experiment, in contrast to the traditional method that provides one point on the flux curve from each test. The new methods lay the foundation of rapid flux identification; however, experimental procedures need to be elaborated.

Conidiobolus pachyzygosporus invasive pulmonary infection in a patient with acute myeloid leukemia: case report and review of the literature.

BACKGROUND: Conidiobolus spp. (mainly C. coronatus) are the causal agents of rhino-facial conidiobolomycosis, a limited soft tissue infection, which is essentially observed in immunocompetent individuals from tropical areas. Rare cases of invasive conidiobolomycosis due to C. coronatus or other species (C.incongruus, C.lamprauges) have been reported in immunocompromised patients. We report here the first case of invasive pulmonary fungal infection due to Conidiobolus pachyzygosporus in a Swiss patient with onco-haematologic malignancy. CASE PRESENTATION: A 71 year-old female was admitted in a Swiss hospital for induction chemotherapy of acute myeloid leukemia. A chest CT performed during the neutropenic phase identified three well-circumscribed lung lesions consistent with invasive fungal infection, along with a positive 1,3-beta-d-glucan assay in serum. A transbronchial biopsy of the lung lesions revealed large occasionally septate hyphae. A Conidiobolus spp. was detected by direct 18S rDNA in the tissue biopsy and subsequently identified at species level as C. pachyzygosporus by 28S rDNA sequencing. The infection was cured after isavuconazole therapy, recovery of the immune system and surgical resection of lung lesions. CONCLUSIONS: This is the first description of C. pachyzygosporus as human pathogen and second case report of invasive conidiobolomycosis from a European country.

Contrasting indoor and ambient particulate matter concentrations and thermal comfort in coal and non-coal burning households at South Africa Highveld.

One of the key challenges noted in the sustainable development goals for good health and wellbeing (SDGs 3) is both ambient and household air pollution. Household solid fuel combustion represents one of the biggest threat to human health in South Africa. This study helps to understand the impact of solid fuel burning in an indoor and ambient environment. Continuous monitoring of particulate matter (PM4) was carried out in two houses, one used coal as a primary source of energy, while the other did not. For solid fuel burning (SFB) house the winter PM4 average 24-h concentration ranges between 60.9 µg m-3 and 207.5 µg m-3 while at non-solid fuel burning (NSFB) house it ranges between 15.3 µg m-3 and 84.2 µg m-3. In both houses, the national ambient air quality standard (NAAQS) for PM2.5 (40 µg m-3) were exceeded during winter. The summer PM4 levels ranged between 17.4 µg m-3 and 36.6 µg m-3 in the solid fuel burning house and between 14.2 µg m-3 and 39.9 µg m-3 at the non-solid fuel-burning house. During mornings and evenings, indoor concentrations were higher than the outdoor; these periods coincide with the fuel-burning pattern in this community. In the mid-afternoon, the outdoor PM levels sometimes went higher than the indoor levels, perhaps as a result of the pollution from the power plants in the neighbourhood. Using the linear regression model, there were no significant correlations between indoor/outdoor PM4 concentrations during the winter, but there were good correlations for both houses during the summer. There was an observed difference in the thermal comfort at the SFB and NSFB. The temperature at SFB went below the World Health Organisation standard in winter and above during the summer while at NSFB, the temperature was managed within the standard in both seasons.

Effect of patient education on palliative care knowledge and acceptability of outpatient palliative care services among gynecologic oncology patients: A randomized controlled trial.

OBJECTIVES: A randomized control trial (RCT) to estimate the effect of an interventional video on improving palliative care knowledge, acceptability and attendance to outpatient services in gynecologic oncology patients. METHODS: Women receiving treatment for gynecologic malignancy recruited at an academic tertiary care center were randomized to: palliative care educational video or non-directive cancer center video. The primary outcome was referral to palliative care. Function and knowledge were assessed using the Functional Assessment of Cancer Therapy and the Palliative Care Knowledge Scale. Data analyses were performed using t-tests, Wilcoxon rank sum or Fisher's exact tests with significance level of α = 0.05. RESULTS: 111 women were enrolled. Demographic characteristics were equally distributed between groups with respect to age, race, cancer, and stage. There was no statistical difference in knowledge scores or in referral to palliative care between the patients that watched the educational versus control video (29% vs. 27%; p = .79). Secondary analysis showed a statistically significant increase in utilization of palliative care services compared to historic institutional data (8.8% to 31.5%; p ≤.001). Further, those referred had significantly worse baseline functional scores. CONCLUSIONS: Use of a palliative care educational video did not increase knowledge or acceptability of palliative services within this RCT. However, the rate of patients referred to palliative care tripled compared to historic rates. Further studies should investigate whether discussion regarding palliative care services alone may increase desire for referral, and if use of Fact-G scores may identify patients in greatest need of services.

Measurements of adiposity as prognostic biomarkers for survival with anti-angiogenic treatment in epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group ancillary data analysis of GOG 218.

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.

Effects and determinants of tuberculosis drug stockouts in South Africa.

BACKGROUND: The frequent occurrence of medicine stockouts represents a significant obstacle to tuberculosis control in South Africa. Stockouts can lead to treatment alterations or interruptions, which can impact treatment outcomes. This study investigates the determinants and effects of TB drug stockouts and whether poorer districts are disproportionately affected. METHODS: TB stockout data, health system indicators and TB treatment outcomes at the district level were extracted from the District Health Barometer for the years 2011, 2012 and 2013. Poverty terciles were constructed using the Census 2011 data to investigate whether stockouts and poor treatment outcomes were more prevalent in more impoverished districts. Fixed-effects regressions were used to estimate the effects of TB stockouts on TB treatment outcomes. RESULTS: TB stockouts occurred in all provinces but varied across provinces and years. Regression analysis showed a significant association between district per capita income and stockouts: a 10% rise in income was associated with an 8.50% decline in stockout proportions. In terms of consequences, after controlling for unobserved time invariant heterogeneity between districts, a 10% rise in TB drug stockouts was found to lower the cure rate by 2.10% (p < 0.01) and the success rate by 1.42% (p < 0.01). These effects were found to be larger in poorer districts. CONCLUSIONS: The unequal spread of TB drug stockouts adds to the socioeconomic inequality in TB outcomes. Not only are stockouts more prevalent in poorer parts of South Africa, they also have a more severe impact on TB treatment outcomes in poorer districts. This suggests that efforts to cut back TB drug stockouts would not only improve TB treatment outcomes on average, they are also likely to improve equity because a disproportionate share of this burden is currently borne by the poorer districts.