Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets.

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Respiratory Syncytial Virus-Associated Hospitalizations in Children <5 Years: 2016-2022.

BACKGROUND: The coronavirus disease 2019 pandemic disrupted respiratory syncytial virus (RSV) seasonality resulting in early, atypical RSV seasons in 2021 and 2022, with an intense 2022 peak overwhelming many pediatric healthcare facilities. METHODS: We conducted prospective surveillance for acute respiratory illness during 2016-2022 at 7 pediatric hospitals. We interviewed parents, reviewed medical records, and tested respiratory specimens for RSV and other respiratory viruses. We estimated annual RSV-associated hospitalization rates in children aged <5 years and compared hospitalization rates and characteristics of RSV-positive hospitalized children over 4 prepandemic seasons (2016-2020) to those hospitalized in 2021 or 2022. RESULTS: There was no difference in median age or age distribution between prepandemic and 2021 seasons. Median age of children hospitalized with RSV was higher in 2022 (9.6 months vs 6.0 months, P < .001). RSV-associated hospitalization rates were higher in 2021 and 2022 than the prepandemic average across age groups. Comparing 2021 to 2022, RSV-associated hospitalization rates were similar among children <2 years of age; however, children aged 24 to 59 months had significantly higher rates of RSV-associated hospitalization in 2022 (rate ratio 1.68 [95% confidence interval 1.37-2.00]). More RSV-positive hospitalized children received supplemental oxygen and there were more respiratory virus codetections in 2022 than in prepandemic seasons (P < .001 and P = .003, respectively), but there was no difference in the proportion hypoxemic, mechanically ventilated, or admitted to intensive care. CONCLUSIONS: The atypical 2021 and 2022 RSV seasons resulted in higher hospitalization rates with similar disease severity to prepandemic seasons.

Teleneurology and Artificial Intelligence in Clinical Practice.

ABSTRACT: As teleheath becomes integrated into the practice of medicine, it is important to understand the benefits, limitations, and variety of applications. Telestroke was an early example of teleneurology that arose from a need for urgent access to neurologists for time-sensitive treatments for stroke. It made a scarce resource widely available via video conferencing technologies. Additionally, applications such as outpatient video visits, electronic consultation (e-consult), and wearable devices developed in neurology, as well. Telehealth dramatically increased during the COVID-19 pandemic when offices were closed and hospitals were overwhelmed; a multitude of both outpatient and inpatient programs developed and matured during this time. It is helpful to explore what has been learned regarding the quality of telehealth, disparities in care, and how artificial intelligence can interact with medical practices in the teleneurology context.

Surgical Approach Does Not Influence Instability Risk in Revision Total Hip Arthroplasty.

BACKGROUND: Although the direct anterior (DA) approach has increased in popularity for primary total hip arthroplasty (THA), there is limited evidence regarding its use for revision THA. It is unknown whether the dislocation benefit seen in the primary setting translates to revision cases. METHODS: This retrospective review compared the dislocation rates of revision THA performed through DA versus postero-lateral (PL) approaches at a single institution (2011 to 2021). Exclusion criteria included revision for instability, ≥ 2 prior revisions, approaches other than DA or PL, and placement of dual-mobility or constrained liners. There were 182 hips in 173 patients that met inclusion criteria. The average follow-up was 6.5 years (range, 2 to 8 years). RESULTS: There was a trend towards more both-component revisions being performed through the PL approach. There were no differences in dislocation rates between the DA revision and PL revision cohorts, which were 8.1% (5 of 72) and 7.5% (9 of 120), respectively (P = 0.999). Dislocation trended lower when the revision approach was discordant from the primary approach compared to cases where primary and revision had a concordant approach (4.9 versus 8.5%), but this was not statistically significant (P = 0.740). No significant differences were found in return to operating room (OR), 90-day emergency department (ED) visits, or 90-day readmissions. However, the length of stay was significantly shorter in patients who had DA revisions after a primary PL procedure (P = 0.021). CONCLUSION: Dislocation rates following revision THA did not differ between the DA and PL approaches irrespective of the primary approach. Surgeons should choose their revision approach based on their experience and the specific needs of the patient.

Management of Cochlear Implant Electrode Arrays Misplaced in the Internal Auditory Canal: A Systematic Review.

OBJECTIVE: Misplacement of electrode arrays in the internal auditory canal (IAC) presents a unique clinical challenge. Speech recognition is limited for cochlear implant (CI) users with misplaced arrays, and there are risks with revision surgery including facial and/or cochlear nerve injury. DATABASES REVIEWED: PubMed, Embase, and Scopus. METHODS: A literature search was performed from inception to September 2023. The search terms were designed to capture articles on misplaced arrays and the management options. Articles written in English that described cases of array misplacement into the IAC for children and adults were included. The level of evidence was assessed using Oxford Center for Evidence Based Medicine guidelines. Descriptive statistical analyses were performed. RESULTS: Twenty-eight cases of arrays misplaced in the IAC were identified. Thirteen (46%) were patients with incomplete partition type 3 (IP3), and 7 (25%) were patients with common cavity (CC) malformations. Most misplaced arrays were identified postoperatively (19 cases; 68%). Of these cases, 11 (58%) were managed with array removal. No facial nerve injuries were reported with revision surgery. Eight cases (42%) were left in place. Several underwent mapping procedures in an attempt improve the sound quality with the CI. CONCLUSION: Electrode array misplacement in the IAC is a rare complication that reportedly occurs predominately in cases with IP3 and CC malformations. Removal of misplaced arrays from the IAC reportedly has not been associated with facial nerve injuries. Cases identified with IAC misplacement postoperatively can potentially be managed with modified mapping techniques before proceeding with revision surgery.

Recommendations for Tumor Mutational Burden Assay Validation and Reporting: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, and Society for Immunotherapy of Cancer.

Tumor mutational burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in several tumor types. Several laboratories offer TMB testing, but there is significant variation in how TMB is calculated, reported, and interpreted among laboratories. TMB standardization efforts are underway, but no published guidance for TMB validation and reporting is currently available. Recognizing the current challenges of clinical TMB testing, the Association for Molecular Pathology convened a multidisciplinary collaborative working group with representation from the American Society of Clinical Oncology, the College of American Pathologists, and the Society for the Immunotherapy of Cancer to review the laboratory practices surrounding TMB and develop recommendations for the analytical validation and reporting of TMB testing based on survey data, literature review, and expert consensus. These recommendations encompass pre-analytical, analytical, and postanalytical factors of TMB analysis, and they emphasize the relevance of comprehensive methodological descriptions to allow comparability between assays.

Early Effects of the COVID-19 Pandemic on Patients in a Virtual Multicenter Spontaneous Coronary Artery Dissection (SCAD) Registry.

Background: The COVID-19 pandemic effects among patients with a history of spontaneous coronary artery dissection (SCAD), a cause of acute coronary syndrome associated with emotional and physical stress, are unknown. Methods: For this cross-sectional cohort study, participants of the Mayo Clinic "Virtual" Multicenter SCAD Registry were surveyed about the COVID-19 pandemic. Results: Among 1352 participants, 727 (53.8%) completed surveys between June 2, 2021 and September 29, 2021. The majority of respondents (96.7%) were female, with a mean age of 54.9 ± 9.4 years. At the time of completing the survey, which was early in the pandemic, 91 respondents (12.6%) reported having prior COVID-19 symptoms, with < 1% experiencing hospitalization (n = 4) or cardiac complications (n = 6). A total of 14% had ≥ moderate anxiety symptoms, per the General Anxiety Disorder-7 item survey, and 11.8% had ≥ moderate depressive symptoms, per the Patient Health Questionnaire-9 item. Higher stress scores on the Likert scale were correlated with pandemic-related reduction in work hours and/or pay and/or unemployment (P = 0.013), remote work and/or change of job (P < 0.001), and loss of insurance and/or medical coverage (P = 0.025). A higher anxiety level, as measured on the Likert scale, was correlated with pandemic-related remote work and/or change of job (P = 0.007) and loss of insurance and/or medical coverage (P = 0.008). Since the start of the pandemic, 54% of respondents reported having at least monthly chest pain. Chest pain and COVID symptoms were each associated with higher scores on the General Anxiety Disorder-7 item survey and the Patient Health Questionnaire-9 item. Conclusions: Early in the pandemic, COVID-19 symptoms, hospitalization, and cardiac complications were uncommon among SCAD patients. The burden of anxiety and depressive symptoms was minimal to mild, similar to that in prior reports. Likert-scale measures of stress and anxiety were higher among persons with work and/or pay reduction and/or unemployment, remote work and/or change of job, and loss of insurance and/or medical coverage. Over half of respondents reported experiencing chest pain, which was correlated with depressive and anxiety symptoms, highlighting an overarching clinical need.

Contexte: On ne connaît pas les effets de la pandémie de COVID-19 sur les personnes ayant des antécédents de dissection spontanée de l'artère coronaire (DSAC), une cause du syndrome coronarien aigu qui est une source de stress physique et émotionnel. Méthodologie: Pour les besoins de cette étude de cohorte transversale, les participants au registre « virtuel ¼ multicentrique sur la DSAC de la clinique Mayo ont été interrogés dans le cadre d'une enquête sur la pandémie de COVID-19. Résultats: Parmi les 1 352 participants au registre, 727 (53,8 %) ont répondu à l'enquête entre le 2 juin et le 29 septembre 2021. La majorité des répondants (96,7 %) étaient des femmes, et l'âge moyen était de 54,9 ± 9,4 ans. Au moment de l'enquête, réalisée au début de la pandémie, 91 répondants (12,6 %) avaient indiqué avoir déjà présenté des symptômes de COVID-19, et < 1 % avaient été hospitalisés (n = 4) ou avaient présenté des complications cardiaques (n = 6). Au total, 14 % des participants présentaient des symptômes d'anxiété à tout le moins modérés d'après le questionnaire GAD-7 (General Anxiety Disorder-7 item) et 11,8 %, des symptômes dépressifs à tout le moins modérés d'après le questionnaire PHQ-9 (Patient Health Questionnaire-9 item). Une corrélation a été établie entre un score de stress plus élevé sur une échelle de Likert et une réduction des heures de travail et/ou du salaire, une période de chômage (p = 0,013), le télétravail et/ou un changement d'emploi (p < 0,001) et la perte de l'assurance et/ou de la couverture médicale (p = 0,025) en lien avec la pandémie. Une corrélation a également été établie entre un niveau d'anxiété plus élevé mesuré sur une échelle de Likert et le télétravail et/ou un changement d'emploi (p = 0,007) et la perte de l'assurance et/ou de la couverture médicale (p = 0,008) en lien avec la pandémie. Depuis le début de la pandémie, 54 % des répondants ont indiqué ressentir une douleur thoracique au moins une fois par mois. La douleur thoracique et les symptômes de la COVID-19 ont par ailleurs été associés à des scores plus élevés aux questionnaires GAD-7 et PHQ-9. Conclusions: Au début de la pandémie, les symptômes de la COVID-19, les hospitalisations et les complications cardiaques n'étaient pas fréquents chez les patients présentant une DSAC. Le fardeau des symptômes anxieux et dépressifs allait de minime à léger, comme en faisaient état les rapports précédents. L'anxiété et le stress mesurés sur une échelle de Likert ont été plus élevés chez les personnes ayant connu une réduction des heures de travail et/ou du salaire ou une période de chômage, ayant dû recourir au télétravail et/ou changer d'emploi, ou ayant perdu leur assurance et/ou couverture médicale. Plus de la moitié des répondants ont indiqué ressentir une douleur thoracique, laquelle a été mise en corrélation avec les symptômes d'anxiété et de dépression, ce qui souligne l'existence d'un besoin clinique important.

Motion-Accommodating Dual-Layer Hydrogel Dressing to Deliver Adipose-Derived Stem Cells to Wounds.

BACKGROUND: Current dressing materials cannot secure a cell survival-promoting wound environment for stem cell delivery due to insufficient assimilation to skin motion. The authors developed a novel motion-accommodating dual-layer hydrogel dressing for stem cell delivery into such wounds. METHODS: Dorsal hand skin movement was evaluated to determine the potential range of deformation for a dressing. The outer hydrogel (OH) was fabricated with an alginate-acrylamide double-network hydrogel with a covalently cross-linked elastomer coat. The tough adhesive consisted of a chitosan-based bridging polymer and coupling reagents. OH material properties and adhesiveness on porcine skin were measured. An oxidized alginate-based inner hydrogel (IH) containing human adipose-derived stem cells (ASCs) was evaluated for cell-supporting and cell-releasing properties. The OH's function as a secondary dressing, and dual-layer hydrogel cell delivery potential in wounds were assessed in a rodent model. RESULTS: The dual-layer hydrogel consisted of OH and IH. The OH target range of deformation was up to 25% strain. The OH adhered to porcine skin, and showed significantly higher adhesion energy than common secondary dressings and endured 900 flexion-extension cycles without detachment. OH showed a similar moisture vapor transmission rate as moisture-retentive dressings. IH maintained embedded cell survival for three days with significant cell release on the contacting surface. OH showed less fibrotic wound healing than other secondary dressings in vivo. The dual-layer hydrogel successfully delivered ASCs into open wounds of nude mice (13 ± 3 cells/HPF). CONCLUSIONS: The novel dual-layer hydrogel can accommodate patient movement and deliver ASCs into the wound bed by securing the wound microenvironment.

Improving preparedness for introducing and scaling up long-acting HIV pre-exposure prophylaxis in Asia.

Long-acting injectable PrEP, particularly cabotegravir (CAB-LA), has the potential to enhance HIV prevention in Asia, and was the topic of a roundtable held in Singapore in June 2023. Despite proven efficacy, CAB-LA's impact in Asia is hindered by regulatory, manufacturing, and cost barriers. There is an urgent need to address these challenges to expedite CAB-LA's introduction and scale-up, including collaborative research, streamlined regulatory processes, and increased manufacturing capacity. We call for better preparedness in long-acting PrEP in research and implementation science, product licensing and accessibility, and capacity readiness for scale-up, to meet the significant demand among key populations in Asia.

Beyond co-expression: pathway discovery for plant pharmaceuticals.

Plant natural products have been an important source of medicinal molecules since ancient times. To gain access to the whole diversity of these molecules for pharmaceutical applications, it is important to understand their biosynthetic origins. Whilst co-expression is a reliable tool for identifying gene candidates, a variety of complementary methods can aid in screening or refining candidate selection. Here, we review recently employed plant biosynthetic pathway discovery approaches, and highlight future directions in the field.

Mitigating Toxic Metal Exposure Through Leafy Greens: A Comprehensive Review Contrasting Cadmium and Lead in Spinach.

Metals and metalloids (hereafter, metal(loid)s) in plant-based foods are a source of exposure to humans, but not all metal(loid)-food interactions are the same. Differences exist between metal(loid)s in terms of their behavior in soils and in how they are taken up by plants and stored in the edible plant tissue/food. Thus, there cannot be one consistent solution to reducing toxic metal(loid)s exposure to humans from foods. In addition, how metal(loid)s are absorbed, distributed, metabolized, and excreted by the human body differs based on both the metal(loid), other elements and nutrients in the food, and the nutritional status of the human. Initiatives like the United States Food and Drug Administration's Closer to Zero initiative to reduce the exposure of young children to the toxic elements cadmium, lead, arsenic, and mercury from foods warrant careful consideration of each metal(loid) and plant interaction. This review explores such plant-metal(loid) interactions using the example of spinach and the metals cadmium and lead. This review highlights differences in the magnitude of exposure, bioavailability, and the practicality of mitigation strategies while outlining research gaps and future needs. A focus on feasibility and producer needs, informed via stakeholder interviews, emphasizes the need for better analytical testing facilities and grower and consumer education. More research should focus on minimization of chloride inputs for leafy greens to lessen plant-availability of Cd and the role of oxalate in reducing Cd bioavailability from spinach. These findings are applicable to other leafy greens (e.g., kale, lettuce), but not for other plants or metal(loid)s.

Disruption in glutathione metabolism and altered energy production in the liver and kidney after ischemic acute kidney injury in mice.

Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.

Longitudinal Changes in Kidney Solute Clearance in a Prospective Cohort of Patients Initiating Chronic Hemodialysis.

Introduction: Longitudinal changes in residual kidney function have not been well-examined in patients starting chronic hemodialysis (HD). Methods: We analyzed urine volume and kidney solute clearances from timed urine collections and corresponding plasma samples from 42 patients randomized to incremental HD (n = 21) and conventional HD (n = 21) in the TwoPlus pilot study. Samples were collected before HD initiation (baseline); and at 6, 12, 24, and 48 weeks. We assessed temporal trends in urine volume, kidney urea and creatinine clearance, and correlations between urine volume and kidney solute clearance. Results: Residual kidney function parameters in all patients declined over time; the pattern of decline differed between urine volume and kidney solute clearances. Urine volume declined at a steady rate with median (quartile 1, quartile 3) percentage change relative to baseline of -10% (-36 to 29) at week 6 and -47% (-76 to 5) by week 48. Kidney urea and creatinine clearances exhibited a larger decline than urine volume at week 6, -32% (-61 to 8) and -47% (-57 to -20), respectively. The rate of decline subsequently slowed, reaching about 61% decline for both solutes by week 48. Conventional HD demonstrated larger declines in urine volume and kidney urea clearance than incremental HD at week 6. Urine volume showed moderate correlation with urea (R = 0.47) and weaker correlation with creatinine (R = 0.34). Conclusion: Despite gradual decrement in urine volume and kidney solute clearances, residual kidney function persists nearly 1 year after HD initiation. This knowledge could motivate increased practice of individualizing HD prescriptions by incorporating residual kidney function.

Resurrecting Hitomi for Decaying Dark Matter and Forecasting Leading Sensitivity for XRISM.

The Hitomi x-ray satellite mission carried unique high-resolution spectrometers that were set to revolutionize the search for sterile neutrino dark matter (DM) by looking for narrow x-ray lines arising from DM decays. Unfortunately, the satellite was lost shortly after launch, and to date the only analysis using Hitomi for DM decay used data taken towards the Perseus cluster. In this work we present a significantly more sensitive search from an analysis of archival Hitomi data towards blank sky locations, searching for DM decaying in our own Milky Way. The recently launched XRISM satellite has nearly identical soft-x-ray spectral capabilities to Hitomi; we project the full-mission sensitivity of XRISM for analyses of their future blank-sky data, and we find that XRISM will have the leading sensitivity to decaying DM for masses between roughly 1 to 18 keV, with important implications for sterile neutrino and heavy axionlike particle DM scenarios.

Longitudinal Evaluation of Atrial Function in Patients with Tetralogy of Fallot.

Atrial function provides insight into ventricular diastolic function. Invasive assessment of left ventricular (LV) diastolic function correlates with development of sustained ventricular tachyarrhythmias in patients with repaired tetralogy of Fallot (rTOF). Non-invasive assessment of atrial function may prove key towards assessment of diastolic function. We longitudinally evaluated the progression of biatrial function in patients with rTOF, regardless of pulmonary valve replacement (PVR). Patients with rTOF who had multiple CMR were identified. CMR examinations were retrospectively reviewed. Left (LA) and right (RA) atrial size and function were measured in the two and four-chamber views and assessed over time and after PVR. Left and right atrial reservoir, conduit, pump strain and strain rates were determined using tissue tracking. Thirty-six patients with rTOF were identified (64% male), ten (28%) had PVR during the study. Median age of PVR was 16.5 years. No improvement in RA or LA function was observed after PVR. A decline in RA reservoir strain rate (p < 0.05) and RA pump strain (p < 0.05) were observed despite improvements in right ventricular systolic function (p < 0.05). In patients who had multiple CMR without PVR, RA reservoir strain rate (p < 0.05) and pump strain rate (p < 0.05) worsened over time. LA pump strain decreased over time in all patients. There is progressive decline of several RA functional parameters over time. No significant improvement in LA or RA function after PVR was observed. Additional studies are needed to understand how these changes may relate to poor outcomes and potentially better guide timing of PVR.

Single-Shot Standoff Hyperspectral Raman Imaging of a Chemical Warfare Agent Simulant.

We demonstrate single-shot standoff hyperspectral Raman imaging of liquid diisopropyl methylphosphonate at a standoff distance of 1 m using two different techniques: multi-bandpass filter imaging (MBFI) and fiber-bundle imaging spectroscopy (FBIS). We find that MBFI has good spatial resolution, but poor spectral resolution, due to the limitations of commercially available bandpass filters. On the other hand, we find FBIS to have excellent spectral resolution, but limited spatial resolution due to the relatively small number of fibers in a bundle. For FBIS, we also determine, for a 1 m standoff distance, a minimum pump fluence of 10 mJ/cm2 to obtain good single-shot spectra.

Influence of hypercapnia and hypercapnic hypoxia on the heart rate response to apnea.

We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty-six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (-19 ± 16 bpm) than normocapnic normoxic apneas (-11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (-19 ± 15 bpm; p = 0.999) and hypercapnic apneas (-14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (-11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (-9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia.

Genetic identification of medullary neurons underlying congenital hypoventilation.

Mutations in the transcription factors encoded by PHOX2B or LBX1 correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO2. The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.

Health literacy & Chagas disease knowledge: A cross-sectional study in Southern Loja Province, Ecuador.

Objective: Health literacy is associated with many patient outcomes. This study sought to determine the association between a person's level of health literacy and their knowledge about Chagas disease. Methods: A cross-sectional survey was conducted with people living in two counties in rural Loja Province, Ecuador who attended a mobile health clinic. The communities in which the study was conducted are at high risk of Chagas disease and have limited access to both health care and educational resources. The Spanish version of Short Assessment for Health Literacy measured health literacy. The Chagas Disease Knowledge questionnaire measured knowledge of Chagas disease. T-tests and correlational analysis were used to assess associations. Results: Overall 85 people participated in this study. A majority of the respondents were female (64.1%), and a plurality were married (40.7%) and had education less than secondary (40.7%). The average age of the sample was 44.31 ± 18.85. Health literacy levels and Chagas disease knowledge in the communities were low. About half of people had inadequate health literacy. No association between health literacy and Chagas knowledge was found. Conclusion: Health literacy levels and Chagas disease knowledge were not found to be correlated. Explanations for the lack of association may include common causes of inadequate investment in Chagas disease education as well as neglect of health systems in rural Ecuador. Efforts to improve both health literacy and Chagas disease knowledge in poorer, rural areas of Ecuador are needed. Innovation: This is the first study to assess relationships between health literacy and knowledge of Chagas disease in an uninfected population. For novel conditions, relationships between health literacy and disease knowledge should be investigated before communication campaigns are adapted.