Prediction models for post-discharge mortality among under-five children with suspected sepsis in Uganda: A multicohort analysis.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Morphological remodeling of Coxiella burnetii during its biphasic developmental cycle revealed by cryo-electron tomography.

Coxiella burnetii is an obligate zoonotic bacterium that targets macrophages causing a disease called Q fever. It has a biphasic developmental life cycle where the extracellular and metabolically inactive small cell variant (SCV) transforms inside the host into the vegetative large cell variant (LCV). However, details about the morphological and structural changes of this transition are still lacking. Here, we used cryo-electron tomography to image both SCV and LCV variants grown either under axenic conditions or purified directly from host cells. We show that SCVs are characterized by equidistant stacks of inner membrane that presumably facilitate the transition to LCV, a transition coupled with the expression of the Dot/Icm type IVB secretion system (T4BSS). A class of T4BSS particles were associated with extracellular densities possibly involved in host infection. Also, SCVs contained spherical multilayered membrane structures of different sizes and locations suggesting no connection to sporulation as once assumed.

Mortality after hospital discharge among children younger than 5 years admitted with suspected sepsis in Uganda: a prospective, multisite, observational cohort study.

BACKGROUND: Substantial mortality occurs after hospital discharge in children younger than 5 years with suspected sepsis, especially in low-income countries. A better understanding of its epidemiology is needed for effective interventions to reduce child mortality in these countries. We evaluated risk factors for death after discharge in children admitted to hospital for suspected sepsis in Uganda, and assessed how these differed by age, time of death, and location of death. METHODS: In this prospective, multisite, observational cohort study, we recruited and consecutively enrolled children aged 0-60 months admitted with suspected sepsis from the community to the paediatric wards of six Ugandan hospitals. Suspected sepsis was defined as the need for admission due to a suspected or proven infectious illness. At admission, trained study nurses systematically collected data on clinical variables, sociodemographic variables, and baseline characteristics with encrypted study tablets. Participants were followed up for 6 months after discharge by field officers who contacted caregivers at 2 months and 4 months after discharge by telephone and at 6 months after discharge in person to measure vital status, health-care seeking after discharge, and readmission details. We assessed 6-month mortality after hospital discharge among those discharged alive, with verbal autopsies conducted for children who had died after hospital discharge. FINDINGS: Between July 13, 2017, and March 30, 2020, 16 991 children were screened for eligibility. 6545 children (2927 [44·72%] female children and 3618 [55·28%] male children) were enrolled and 6191 were discharged from hospital alive. 6073 children (2687 [44·2%] female children and 3386 [55·8%] male children) completed follow-up. 366 children died in the 6-month period after discharge (weighted mortality rate 5·5%). Median time from discharge to death was 28 days (IQR 9-74). For the 360 children for whom location of death was documented, deaths occurred at home (162 [45·0%]), in transit to care (66 [18·3%]), or in hospital (132 [36·7%]) during a subsequent readmission. Death after hospital discharge was strongly associated with weight-for-age Z scores less than -3 (adjusted risk ratio [aRR] 4·7, 95% CI 3·7-5·8 vs a Z score of >-2), discharge or referral to a higher level of care (7·3, 5·6-9·5), and unplanned discharge (3·2, 2·5-4·0). Hazard ratios (HRs) for severe anaemia (<7g/dL) increased with time since discharge, from 1·7 (95% CI 0·9-3·0) for death occurring in the first time tertile to 5·2 (3·1-8·5) in the third time tertile. HRs for some discharge vulnerabilities decreased significantly with increasing time since discharge, including unplanned discharge (from 4.5 [2·9-6·9] in the first tertile to 2·0 [1·3-3·2] in the third tertile) and poor feeding status (from 7·7 [5·4-11·0] to 1·84 [1·0-3·3]). Age interacted with several variables, including reduced weight-for-age Z score, severe anaemia, and reduced admission temperature. INTERPRETATION: Paediatric mortality following hospital discharge after suspected sepsis is common, with diminishing, although persistent, risk during the first 6 months after discharge. Efforts to improve outcomes after hospital discharge are crucial to achieving Sustainable Development Goal 3.2 (ending preventable childhood deaths under age 5 years). FUNDING: Grand Challenges Canada, Thrasher Research Fund, BC Children's Hospital Foundation, and Mining4Life.

Identification of Type 4B Secretion System Substrates That Are Conserved among Coxiella burnetii Genomes and Promote Intracellular Growth.

Coxiella burnetii is a Gram-negative pathogen that infects a variety of mammalian hosts. Infection of domesticated ewes can cause fetal abortion, whereas acute human infection normally manifests as the flu-like illness Q fever. Successful host infection requires replication of the pathogen within the lysosomal Coxiella-containing vacuole (CCV). The bacterium encodes a type 4B secretion system (T4BSS) that delivers effector proteins into the host cell. Disruption of C. burnetii T4BSS effector export abrogates CCV biogenesis and bacterial replication. Over 150 C. burnetii T4BSS substrates have been designated often based on heterologous protein translocation by the Legionella pneumophila T4BSS. Cross-genome comparisons predict that many of these T4BSS substrates are truncated or absent in the acute-disease reference strain C. burnetii Nine Mile. This study investigated the function of 32 proteins conserved among diverse C. burnetii genomes that are reported to be T4BSS substrates. Despite being previously designated T4BSS substrates, many of the proteins were not translocated by C. burnetii when expressed fused to the CyaA or BlaM reporter tags. CRISPR interference (CRISPRi) indicated that of the validated C. burnetii T4BSS substrates, CBU0122, CBU1752, CBU1825, and CBU2007 promote C. burnetii replication in THP-1 cells and CCV biogenesis in Vero cells. When expressed in HeLa cells tagged at its C or N terminus with mCherry, CBU0122 localized to the CCV membrane and the mitochondria, respectively. Collectively, these data further define the repertoire of bona fide C. burnetii T4BSS substrates. IMPORTANCE Coxiella burnetii secretes effector proteins via a T4BSS that are required for successful infection. Over 150 C. burnetii proteins are reported to be T4BSS substrates and often by default considered putative effectors, but few have assigned functions. Many C. burnetii proteins were designated T4BSS substrates using heterologous secretion assays in L. pneumophila and/or have coding sequences that are absent or pseudogenized in clinically relevant C. burnetii strains. This study examined 32 previously reported T4BSS substrates that are conserved among C. burnetii genomes. Of the proteins tested that were previously designated T4BSS substrates using L. pneumophila, most were not exported by C. burnetii. Several T4BSS substrates that were validated in C. burnetii also promoted pathogen intracellular replication and one trafficked to late endosomes and the mitochondria in a manner suggestive of effector activity. This study identified several bona fide C. burnetii T4BSS substrates and further refined the methodological criteria for their designation.

Semantic focus mediates pitch auditory feedback control in phrasal prosody.

This study investigated the effect of semantic focus on pitch auditory feedback control in the production of phrasal prosody through an experiment using pitch-shifted auditory feedback. We hypothesized that pitch-shift responses would be mediated by semantic focus because highly informative focus types, such as corrective focus, impose more specific constraints on the prosodic form of a phrase and require greater consistency in the production of pitch excursions compared to sentences with no such focus elements. Twenty-eight participants produced sentences with and without corrective focus while their auditory feedback was briefly and unexpectedly perturbed in pitch by +/-200 cents at the start of the sentence. The magnitude and latency of the reflexive pitch-shift responses were measured as a reflection of auditory feedback control. Our results matched our prediction that corrective focus would elicit larger pitch-shift responses, supporting our hypothesis that auditory feedback control is mediated by semantic focus.

Effect of school-based nutrition interventions among primary school children in sub-Saharan Africa: a systematic review protocol.

INTRODUCTION: Preadolescents are passing through an intensive growth and development period that will benefit from healthy eating practices. For those attending school, school environments offer several potential benefits and have been demonstrated to influence the quality of dietary intakes and consequentially, nutritional status of school-aged children (SAC). Considering the amount of time children spend in school and the enormous potential of evidence-based interventions, the purpose of this review is to critically appraise peer-reviewed literature addressing the impact of school-based interventions on the nutritional status of SAC aged 6-12 years in sub-Saharan Africa. METHODS AND ANALYSIS: A systematic search will be conducted in the following databases and online search records: Medline, CINAHL, Web of Science, Embase, Global health, Global Index Medicus, Cochrane library, Hinari and Google Scholar using search terms and keywords codeveloped with two librarians. An additional search will also be conducted from the reference list of identified literature. Search results of titles and abstracts will be initially screened for eligibility criteria by two independent reviewers and where there is disagreement, a third reviewer will be consulted. Articles meeting these criteria will then undergo a full-text review for the eligibility and exclusion criteria. The Joanna Briggs Institute critical appraisal tool will be used to assess the risk of bias. Data from articles meeting all study criteria will be extracted, analysed and synthesised. A meta-analysis will also be conducted if sufficient data are available. ETHICS AND DISSEMINATION: This systematic review is limited to publicly accessible data bases not requiring prior ethical approval to access. The results of the systematic review will be disseminated through publications in peer-reviewed journals as well as conference and stakeholder presentations. PROSPERO REGISTRATION NUMBER: CRD42022334829.

A Survey of Two-Component Systems in Coxiella burnetii Reveals Redundant Regulatory Schemes and a Requirement for an Atypical PhoBR System in Mammalian Cell Infection.

Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever in humans. C. burnetii transitions between a replicative, metabolically active large-cell variant (LCV) and a spore-like, quiescent small-cell variant (SCV) as a likely mechanism to ensure survival between host cells and mammalian hosts. C. burnetii encodes three canonical two-component systems, four orphan hybrid histidine kinases, five orphan response regulators, and a histidine phosphotransfer protein, which have been speculated to play roles in the signaling required for C. burnetii morphogenesis and virulence. However, very few of these systems have been characterized. By employing a CRISPR interference system for genetic manipulation of C. burnetii, we created single- and multigene transcriptional knockdown strains targeting most of these signaling genes. Through this, we revealed a role for the C. burnetii PhoBR canonical two-component system in virulence, regulation of [Pi] maintenance, and Pi transport. We also outline a novel mechanism by which PhoBR function may be regulated by an atypical PhoU-like protein. We also determined that the GacA.2/GacA.3/GacA.4/GacS orphan response regulators coordinately and disparately regulate expression of SCV-associated genes in C. burnetii LCVs. These foundational results will inform future studies on the role of C. burnetii two-component systems in virulence and morphogenesis. IMPORTANCE C. burnetii is an obligate intracellular bacterium with a spore-like stability allowing it to survive long periods of time in the environment. This stability is likely due to its biphasic developmental cycle, whereby it can transition from an environmentally stable small-cell variant (SCV) to a metabolically active large-cell variant (LCV). Here, we define the role of two-component phosphorelay systems (TCS) in C. burnetii's ability to survive within the harsh environment contained in the phagolysosome of host cells. We show that the canonical PhoBR TCS has an important role in C. burnetii virulence and phosphate sensing. Further examination of the regulons controlled by orphan regulators indicated a role in modulating gene expression of SCV-associated genes, including genes essential for cell wall remodeling.

Effects of sensorimotor voice training on event-related potentials to pitch-shifted auditory feedback.

The pitch perturbation technique is a validated technique that has been used for over 30 years to understand how people control their voice. This technique involves altering a person's voice pitch in real-time while they produce a vowel (commonly, a prolonged /a/ sound). Although post-task changes in the voice have been observed in several studies (e.g., a change in mean fo across the duration of the experiment), the potential for using the pitch perturbation technique as a training tool for voice pitch regulation and/or modification has not been explored. The present study examined changes in event related potentials (ERPs) and voice pitch in three groups of subjects due to altered voice auditory feedback following a brief, four-day training period. Participants in the opposing group were trained to change their voice fo in the opposite direction of a pitch perturbation stimulus. Participants in the following group were trained to change their voice fo in the same direction as the pitch perturbation stimulus. Participants in the non-varying group did not voluntarily change their pitch, but instead were asked to hold their voice constant when they heard pitch perturbations. Results showed that all three types of training affected the ERPs and the voice pitch-shift response from pre-training to post-training (i.e., "hold your voice pitch steady" task; an indicator of voice pitch regulation). Across all training tasks, the N1 and P2 components of the ERPs occurred earlier, and the P2 component of the ERPs occurred with larger amplitude post-training. The voice responses also occurred earlier but with a smaller amplitude following training. These results demonstrate that participation in pitch-shifted auditory feedback tasks even for brief periods of time can modulate the automatic tendency to compensate for alterations in voice pitch feedback and has therapeutic potential.

The Effect of Pitch and Loudness Auditory Feedback Perturbations on Vocal Quality During Sustained Phonation.

OBJECTIVE: Dysphonia is a reduction in vocal quality that impacts communication and is often an early sign of a voice disorder. There is little information regarding the effects of auditory feedback control of loudness and pitch on voice quality. In this study, we used both loudness-shift and pitch-shift paradigms to study the relationship between auditory feedback control and vocal quality as measured by smoothed cepstral peak prominence (CPPS), which reflects the harmonicity of the voice signal. STUDY DESIGN: Experimental, mixed design. METHODS: We applied 200 ms loudness-shifts (± 0, 3, or 6 dB) and pitch-shifts (± 0, 50, and 100 cents) to auditory feedback during sustained vowel production in 25 healthy adults. We then measured CPPS before and after the loudness-shift or pitch-shift to investigate the effect of changes in auditory feedback on vocal harmonicity. RESULTS & CONCLUSIONS: Results showed that, on average, CPPS significantly decreased between the first half of the measured segment and the last half of the segment in the absence of auditory feedback shifts, suggesting that voice quality may be reduced across longer vowels over time. Upward and downward shifts in loudness auditory feedback caused a relative increase in CPPS, indicating an improvement in vocal harmonicity, even in cases when vocal intensity was reduced. Pitch alterations had inconsistent and minimal effects. We propose that there may be a control mechanism for voice quality that increases harmonicity of the voice signal to improve voice audibility (ie, ability to be heard) in the presence of unpredictable variability in voice intensity.

Auditory-Motor Control of Fundamental Frequency in Vocal Vibrato.

PURPOSE: The purpose of this study was to investigate how classically trained singers use their auditory feedback to control fundamental frequency (fo) during production of vocal vibrato. Two main questions were addressed: (1) Do singers produce reflexive foresponses to sudden perturbation of the fo of their auditory feedback during production of vibrato indicative of feedback control? (2) Do singers produce adaptive foresponses to repeated perturbation of the fo of their auditory feedback during production of vibrato indicative of feedback and feedforward control? In addition, one methodological question was addressed to determine if adaptive fo responses were more precisely assessed with or without an auditory cue for fo during the repeated fo perturbation paradigm. METHOD: Ten classically trained singers produced sustained vowels with vibrato while the fo and harmonics of their auditory feedback were suddenly perturbed by 100 cents to assess reflexive control or repeatedly perturbed by 100 cents to assess adaptive control. Half of the participants completed the repeated perturbation experiment with an auditory cue for fo, and the other half completed the experiment without an auditory cue for fo. Acoustical analyses measured changes in mean fo in response to the auditory feedback perturbations. RESULTS: On average, participants produced compensatory responses to both sudden and repeated perturbation of the fo of their auditory feedback. The magnitude of the responses to repeated perturbations was larger than the responses to sudden perturbations. Responses were also larger in the cued, repeated fo perturbation experiment than in the uncued, repeated fo perturbation experiment. CONCLUSIONS: These findings indicate that classically-trained singers use both feedforward and feedback mechanisms to control their average fo during production of vibrato. When compared to prior studies of singers producing a steady voice, the reflexive fo responses were larger in the current study, which may indicate that the feedback control system is engaged more during production of vibrato.

Deficiency in Re-Orienting of Attention in Adults with Attention-Deficit Hyperactivity Disorder.

Objective: To characterize potential brain indexes of attention deficit hyperactivity disorder (ADHD) in adults. Methods: In an effort to develop objective, laboratory-based tests that can help to establish ADHD diagnosis, the brain indexes of distractibility was investigated in a group of adults. We used event-related brain potentials (ERPs) and performance measures in a forced-choice visual task. Results: Behaviorally aberrant distractibility in the ADHD group was significantly higher. Across three ERP components of distraction: N1 enhancement, P300 (P3a), and Reorienting Negativity (RON) the significant difference between ADHD and matched controls was found in the amplitude of the RON. We used non-parametric randomization tests, enabling us to statistically validated this difference between-group. Conclusions: Our main results of this feasibility study suggest that among other ERP components associated with auditory distraction, the RON response is promising index for a potential biomarker of deficient re-orienting of attention in adults s with ADHD.

Measurement of self-reported, facility-based labour and birth experiences: The Perinatal Experience Assessment Tool (PEAT).

Background: Women and their families make decisions on accessing perinatal care based on their experiences in the health care system and on the experience of others around them. Receiving supportive maternity care which demonstrates respect is an essential part of quality care. Globally, and in low- and middle-income countries in particular, women report receiving mistreatment and a lack of respect during labour, childbirth and the early postnatal period. These experiences, if negative, may influence choices around place of birth, thus hindering the scale-up of facility-based births. Methods: We conducted a focussed review of the literature between 2010 and 2019 to identify recent research addressing the assessment of women's experiences during childbirth in low- and middle-income country facilities. The World Health Organization (WHO) and White Ribbon Alliance themes and concepts of respectful maternity care served as a guide. Themes included disrespectful or abusive experiences such as verbal abuse or rudeness, abandonment, corruption, lack of privacy, failure to respect traditional practices, discrimination, and physical or sexual abuse. Experienced midwives in two low-resource countries contributed to the identification of appropriate indicators of respectful, non-abusive care, and eventual agreement as to which to include in an assessment tool monitoring women's experiences. Results: Our review of the literature identified 18 publications meeting pre-established criteria. This resulted in the eventual selection of 33 indicators of respectful care sub-grouped under 9 domains: 1) communication/verbal interaction, 2) supportive care, 3) physical abuse, 4) non-consented care, 5) non-confidential care/lack of privacy, 6) stigma and discrimination, 7) abandonment/neglect, 8) detention/inability to pay, and 9) health facility conditions. We converted these indicators into questions to be asked by an interviewer during a short interview following discharge to assess the childbirth experience. Conclusions: The Perinatal Experience Assessment Tool (PEAT) may be used to monitor or evaluate the experiences that women report after facility-based childbirth. It can be administered by trained, independent interviewers in the facility following discharge. The PEAT enables maternity leaders to assess the extent to which maternity services are conducted in a respectful, non-abusive manner and modify practices and procedures as feasible and appropriate.

Task-Dependent Modulation of Auditory Feedback Control of Vocal Intensity.

Auditory feedback control of fundamental frequency (fo) is modulated in a task-dependent manner. When voice pitch auditory feedback perturbations are applied in sentence versus sustained-vowel production, larger and faster vocal fo responses are measured in sentence production. This task-dependency reflects the scaling of auditory targets for pitch for the precision required in each speech task. When the range for the pitch auditory target is scaled down for precision (as in the sentence-production task), a greater degree of mismatch is detected from the feedback perturbation and a larger vocal response is measured. The purpose of this study was to determine whether auditory feedback control of vocal intensity is also modulated in a task-dependent manner similar to the control of vocal pitch. Twenty-five English speakers produced repetitions of a sentence and a sustained vowel while hearing their voice auditory feedback briefly perturbed in loudness (+/- 3 or 6 dB SPL, 200 ms duration). The resulting vocal intensity responses were measured, and response magnitudes were robustly larger in the sentence (mean: 1.96 dB) than vowel production (mean: 0.89 dB). Additionally, response magnitudes increased as a function of perturbation magnitude only in sentence production for downward perturbations but decreased in magnitude by perturbation magnitude for upward perturbations. Peak response latencies were robustly shorter in sentence (mean: 184.94 ms) than in vowel production (mean: 214.92 ms). Overall, these results support the hypothesis that auditory feedback control of pitch and loudness are modulated by task and that both pitch and loudness auditory targets are scaled for the precision required for the speaking task.

The Equity Tool for Valuing Global Health Partnerships.

Global health partnerships (GHPs) involve complex relationships between individuals and organizations, often joining partners from high-income and low- or middle-income countries around work that is carried out in the latter. Therefore, GHPs are situated in the context of global inequities and their underlying sociopolitical and historical causes, such as colonization. Equity is a core principle that should guide GHPs from start to end. How equity is embedded and nurtured throughout a partnership has remained a constant challenge. We have developed a user-friendly tool for valuing a GHP throughout its lifespan using an equity lens. The development of the EQT was informed by 5 distinct elements: a scoping review of scientific published peer-reviewed literature; an online survey and follow-up telephone interviews; workshops in Canada, Burkina Faso, and Vietnam; a critical interpretive synthesis; and a content validation exercise. Findings suggest GHPs generate experiences of equity or inequity yet provide little guidance on how to identify and respond to these experiences. The EQT can guide people involved in partnering to consider the equity implications of all their actions, from inception, through implementation and completion of a partnership. When used to guide reflective dialogue with a clear intention to advance equity in and through partnering, this tool offers a new approach to valuing global health partnerships. Global health practitioners, among others, can apply the EQT in their partnerships to learning together about how to cultivate equity in their unique contexts within what is becoming an increasingly diverse, vibrant, and responsive global health community.

The Effects of Masked and Delayed Auditory Feedback on Fundamental Frequency Modulation in Vocal Vibrato.

PURPOSE: Although relatively precise control over the extent and rate of fundamental frequency (fo) modulation may be needed for optimal production of vibrato, the role of auditory feedback in controlling vibrato is not well understood. Previous studies altered the gain and timing of auditory feedback in singers producing vibrato and showed inconsistent effects on the extent and rate of fo modulation, which may have been related to small sample sizes or limited analyses. Therefore, the purpose of this study was to further investigate whether the gain or timing of auditory feedback impacts control of vibrato in a larger sample of speakers and with advanced statistical analyses. METHOD: Ten classically-trained singers produced sustained vowels with vibrato while their auditory feedback was masked with pink noise or multi-talker babble to reduce the gain of their auditory feedback and while their auditory feedback was delayed by about 200 or 300 milliseconds to alter the timing of their auditory feedback. Acoustical analyses measured changes in the extent and rate of fo modulation in the masked and delayed trials relative to control trials. Bayesian modeling was used to analyze the effects of noise-masked, babble-masked, and delayed auditory feedback on the extent and rate of fo modulation. RESULTS: There was compelling evidence that noise masking increased the extent of fo modulation, and babble masking increased the variability in the rate of fo modulation (ie, jitter of fo modulation). Masked auditory feedback did not affect the average rate of fo modulation. Delayed auditory feedback did not affect the extent, rate, or jitter of fo modulation. CONCLUSIONS: The current study demonstrated that reducing the gain of the auditory feedback with noise masking increased the extent of fo modulation but did not affect the average rate of fo modulation in classically-trained singers producing vibrato. Reducing the gain of the auditory feedback with babble masking and altering the timing of auditory feedback with imposed delays did not affect the average extent or rate of fo modulation. However, babble masking increased the jitter of fo modulation rate, which suggests that modulated auditory feedback may affect the periodicity of fo modulation from one modulation cycle to the next. These findings clarify the role of auditory feedback in controlling vibrato and may inform the current reflex-resonance models of vibrato.

Surgical repair of massive hemorrhage secondary to button battery ingestion causing aortoesophageal fistula.

BACKGROUND: In pediatrics, foreign body ingestion poses unique challenges. Each case is unique given variability in timing, type, and size of object, compounded by underlying comorbidities and age. In the mid-1990s, mortality and morbidity associated with button battery (BB) ingestion (BBI) emerged corresponding to modification in battery fabrication towards higher voltage, large-diameter lithium cells. AIMS: To describe the case and management of a BBI in a pediatric patient necessitating the use of cardiopulmonary bypass and deep hypothermic circulatory arrest (DHCA). MATERIALS AND METHODS: A 17-month-old female presented with the sudden loss of consciousness at home. Chest X-ray revealed an esophageal foreign body suspicious for BBI. A massive upper gastrointestinal bleeding was temporized with packing. The patient was urgently taken to the operating room for sternotomy, establishment of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), removal of BB, repair of the left common carotid artery, esophageal, and tracheal injuries. DISCUSSION: Successful management of BBI requires coordinated care and a multidisciplinary approach. A high degree of clinical suspicion for BBI is imperative to facilitate early aggressive interventions. Lateral and anteroposterior chest films should be obtained in any suspected BBI. CONCLUSION: This case demonstrates the utility of CPB and DHCA where control of bleeding secondary to BBI is not otherwise possible.

A Comprehensive Phenotypic Screening Strategy to Identify Modulators of Cargo Translocation by the Bacterial Type IVB Secretion System.

Bacterial type IV secretion systems (T4SSs) are macromolecular machines that translocate effector proteins across multiple membranes into infected host cells. Loss of function mutations in genes encoding protein components of the T4SS render bacteria avirulent, highlighting the attractiveness of T4SSs as drug targets. Here, we designed an automated high-throughput screening approach for the identification of compounds that interfere with the delivery of a reporter-effector fusion protein from Legionella pneumophila into RAW264.7 mouse macrophages. Using a fluorescence resonance energy transfer (FRET)-based detection assay in a bacteria/macrophage coculture format, we screened a library of over 18,000 compounds and, upon vetting compound candidates in a variety of in vitro and cell-based secondary screens, isolated several hits that efficiently interfered with biological processes that depend on a functional T4SS, such as intracellular bacterial proliferation or lysosomal avoidance, but had no detectable effect on L. pneumophila growth in culture medium, conditions under which the T4SS is dispensable. Notably, the same hit compounds also attenuated, to varying degrees, effector delivery by the closely related T4SS from Coxiella burnetii, notably without impacting growth of this organism within synthetic media. Together, these results support the idea that interference with T4SS function is a possible therapeutic intervention strategy, and the emerging compounds provide tools to interrogate at a molecular level the regulation and dynamics of these virulence-critical translocation machines. IMPORTANCE Multi-drug-resistant pathogens are an emerging threat to human health. Because conventional antibiotics target not only the pathogen but also eradicate the beneficial microbiota, they often cause additional clinical complications. Thus, there is an urgent need for the development of "smarter" therapeutics that selectively target pathogens without affecting beneficial commensals. The bacterial type IV secretion system (T4SS) is essential for the virulence of a variety of pathogens but dispensable for bacterial viability in general and can, thus, be considered a pathogen's Achilles heel. By identifying small molecules that interfere with cargo delivery by the T4SS from two important human pathogens, Legionella pneumophila and Coxiella burnetii, our study represents the first step in our pursuit toward precision medicine by developing pathogen-selective therapeutics capable of treating the infections without causing harm to commensal bacteria.

Rottlerin inhibits La Crosse virus-induced encephalitis in mice and blocks release of replicating virus from the Golgi body in neurons.

La Crosse virus (LACV) is a mosquito-borne orthobunyavirus that causes approximately 60 to 80 hospitalized pediatric encephalitis cases in the United States yearly. The primary treatment for most viral encephalitis, including LACV, is palliative care, and specific antiviral therapeutics are needed. We screened the National Center for Advancing Translational Sciences library of 3,833 FDA-approved and bioactive small molecules for the ability to inhibit LACV-induced death in SH-SY5Y neuronal cells. The top three hits from the initial screen were validated by examining their ability to inhibit virus-induced cell death in multiple neuronal cell lines. Rottlerin consistently reduced LACV-induced death by 50% in multiple human and mouse neuronal cell lines with an effective concentration of 0.16-0.69 µg ml-1 depending on cell line. Rottlerin was effective up to 12 hours post-infection in vitro and inhibited virus particle trafficking from the Golgi apparatus to trans-Golgi vesicles. In human inducible pluripotent stem cell-derived cerebral organoids, rottlerin reduced virus production by one log and cell death by 35% compared with dimethyl sulfoxide-treated controls. Administration of rottlerin in mice by intraperitoneal or intracranial routes starting at 3 days post-infection decreased disease development by 30-50%. Furthermore, rottlerin also inhibited virus replication of other pathogenic California serogroup orthobunyaviruses (Jamestown Canyon and Tahyna virus) in neuronal cell lines.

Characterization of Source-Filter Interactions in Vocal Vibrato Using a Neck-Surface Vibration Sensor: A Pilot Study.

PURPOSE: Vocal vibrato is a singing technique that involves periodic modulation of fundamental frequency (fo) and intensity. The physiological sources of modulation within the speech mechanism and the interactions between the laryngeal source and vocal tract filter in vibrato are not fully understood. Therefore, the purpose of this study was to determine if differences in the rate and extent of fo and intensity modulation could be captured using simultaneously recorded signals from a neck-surface vibration sensor and a microphone, which represent features of the source before and after supraglottal vocal tract filtering. METHOD: Nine classically-trained singers produced sustained vowels with vibrato while simultaneous signals were recorded using a vibration sensor and a microphone. Acoustical analyses were performed to measure the rate and extent of fo and intensity modulation for each trial. Paired-samples sign tests were used to analyze differences between the rate and extent of fo and intensity modulation in the vibration sensor and microphone signals. RESULTS: The rate and extent of fo modulation and the extent of intensity modulation were equivalent in the vibration sensor and microphone signals, but the rate of intensity modulation was significantly higher in the microphone signal than in the vibration sensor signal. Larger differences in the rate of intensity modulation were seen with vowels that typically have smaller differences between the first and second formant frequencies. CONCLUSIONS: This study demonstrated that the rate of intensity modulation at the source prior to supraglottal vocal tract filtering, as measured in neck-surface vibration sensor signals, was lower than the rate of intensity modulation after supraglottal vocal tract filtering, as measured in microphone signals. The difference in rate varied based on the vowel. These findings provide further support of the resonance-harmonics interaction in vocal vibrato. Further investigation is warranted to determine if differences in the physiological source(s) of vibrato account for inconsistent relationships between the extent of intensity modulation in neck-surface vibration sensor and microphone signals.

Assessing how global health partnerships function: an equity-informed critical interpretive synthesis.

BACKGROUND: Global health partnerships (GHPs) are situated in complex political and economic relationships and involve partners with different needs and interests (e.g., government agencies, non-governmental organizations, corporations, universities, professional associations, philanthropic organizations and communities). As part of a mixed methods study designed to develop an equity-sensitive tool to support more equity-centred North-South GHPs, this critical interpretive synthesis examined reported assessments of GHPs. RESULTS: We examined 30 peer-reviewed articles for power dynamics, equity and inequities, and contradictions or challenges encountered in North-South partnerships. Among articles reviewed, authors most often situated GHPs around a topical focus on research, capacity-building, clinical, or health services issues, with the 'work' of the partnership aiming to foster skills or respond to community needs. The specific features of GHPs that were assessed varied widely, with consistently-reported elements including the early phases of partnering; governance issues; the day-to-day work of partnerships; the performance, impacts and benefits of GHPs; and issues of inclusion. Articles shared a general interest in partnering processes and often touched briefly on issues of equity; but they rarely accounted for the complexity of sociopolitical and historical contexts shaping issues of equity in GHPs. Further, assessments of GHPs were often reported without inclusion of voices from all partners or named beneficiaries. GHPs were frequently portrayed as inherently beneficial for Southern partners, without attention to power dynamics and inequities (North-South, South-South). Though historical and political dynamics of the Global North and South were inconsistently examined as influential forces in GHPs, such dynamics were frequently portrayed as complex and characterized by asymmetries in power and resources. Generally, assessments of GHPs paid little attention to the macroeconomic forces in the power and resource dynamics of GHPs highlights the importance of considering the broader political. Our findings suggest that GHPs can serve to entrench both inequitable relationships and unfair distributions of power, resources, and wealth within and between countries (and partners) if inequitable power relationships are left unmitigated. CONCLUSIONS: We argue that specific practices could enhance GHPs' contributions to equity, both in their processes and outcomes. Enhancing partnering practices to focus on inclusion, responsiveness to North-South and South-South inequities, and recognition of GHPs as situated in a broader (and inequitable) political economy. A relational and equity-centred approach to assessing GHPs would place social justice, humility and mutual benefits as central practices-that is, regular, routine things that partners involved in partnering do intentionally to make GHPs function well. Practicing equity in GHPs requires continuous efforts to explicitly acknowledge and examine the equity implications of all aspects of partnering.